Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Drug delivery strategies for antibiofilm therapy

Abstract

Although new antibiofilm agents have been developed to prevent and eliminate pathogenic biofilms, their widespread clinical use is hindered by poor biocompatibility and bioavailability, unspecific interactions and insufficient local concentrations. The development of innovative drug delivery strategies can facilitate penetration of antimicrobials through biofilms, promote drug dispersal and synergistic bactericidal effects, and provide novel paradigms for clinical application. In this Review, we discuss the potential benefits of such emerging techniques for improving the clinical efficacy of antibiofilm agents, as well as highlighting the existing limitations and future prospects for these therapies in the clinic.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Sites of common clinical biofilm-associated infections and the most frequent pathogens involved in those infections.
Fig. 2: Challenges associated with treating biofilm-associated infections.
Fig. 3: Mechanisms of action for antibiofilm agents.
Fig. 4: Unique properties and advantages of supramolecular assemblies in treating biofilm-related infections.
Fig. 5: Supramolecular assembly delivery strategies to enhance antimicrobial delivery through the biofilm matrix.

Similar content being viewed by others

References

  1. Murray, C. J. L. et al. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet https://doi.org/10.1016/S0140-6736(21)02724-0.

  2. Taylor, J. et al. Estimating the Economic Costs of Antimicrobial Resistance: Model and Results (RAND Corporation, 2014).

  3. Shrestha, L. B., Baral, R. & Khanal, B. Comparative study of antimicrobial resistance and biofilm formation among Gram-positive uropathogens isolated from community-acquired urinary tract infections and catheter-associated urinary tract infections. Infect. Drug Resist. 12, 957–963 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Editorial. Bold steps to tackle resistance. Nat. Rev. Microbiol. 18, 257 (2020).

    Article  Google Scholar 

  5. Karigoudar, R. M., Karigoudar, M. H., Wavare, S. M. & Mangalgi, S. S. Detection of biofilm among uropathogenic Escherichia coli and its correlation with antibiotic resistance pattern. J. Lab. Physicians 11, 17–22 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Schachter, B. Slimy business — the biotechnology of biofilms. Nat. Biotechnol. 21, 361–365 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. Mah, T.-F. C. & O’Toole, G. A. Mechanisms of biofilm resistance to antimicrobial agents. Trends Microbiol. 9, 34–39 (2001).

    Article  CAS  PubMed  Google Scholar 

  8. Sauer, K. et al. The biofilm life cycle: expanding the conceptual model of biofilm formation. Nat. Rev. Microbiol. 20, 608–620 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Høiby, N. et al. ESCMID guideline for the diagnosis and treatment of biofilm infections 2014. Clin. Microbiol. Infect. 21, S1–S25 (2015).

    Article  PubMed  Google Scholar 

  10. Stacy, A., McNally, L., Darch, S. E., Brown, S. P. & Whiteley, M. The biogeography of polymicrobial infection. Nat. Rev. Microbiol. 14, 93–105 (2016).

    Article  CAS  PubMed  Google Scholar 

  11. Lebeaux, D., Ghigo, J. M. & Beloin, C. Biofilm-related infections: bridging the gap between clinical management and fundamental aspects of recalcitrance toward antibiotics. Microbiol. Mol. Biol. Rev. 78, 510–543 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Anderson, G. G. et al. Intracellular bacterial biofilm-like pods in urinary tract infections. Science 301, 105–107 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. Stewart, P. S. Antimicrobial tolerance in biofilms. Microbiol. Spectr. https://doi.org/10.1128/microbiolspec.MB-0010-2014 (2015).

    Article  PubMed  Google Scholar 

  14. Hall, C. W. & Mah, T.-F. Molecular mechanisms of biofilm-based antibiotic resistance and tolerance in pathogenic bacteria. FEMS Microbiol. Rev. 41, 276–301 (2017).

    Article  CAS  PubMed  Google Scholar 

  15. Lister, J. L. & Horswill, A. R. Staphylococcus aureus biofilms: recent developments in biofilm dispersal. Front. Cell Infect. Microbiol. 4, 178 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Tian, S., van der Mei, H. C., Ren, Y., Busscher, H. J. & Shi, L. Recent advances and future challenges in the use of nanoparticles for the dispersal of infectious biofilms. J. Mater. Sci. Technol. 84, 208–218 (2021).

    Article  CAS  Google Scholar 

  17. Kaplan, J. B. & Fine, D. H. Biofilm dispersal of Neisseria subflava and other phylogenetically diverse oral bacteria. Appl. Environ. Microbiol. 68, 4943–4950 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Whitchurch Cynthia, B., Tolker-Nielsen, T., Ragas Paula, C. & Mattick John, S. Extracellular DNA required for bacterial biofilm formation. Science 295, 1487 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. Buzzo, J. R. et al. Z-form extracellular DNA is a structural component of the bacterial biofilm matrix. Cell 184, 5740–5758.e17 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Seviour, T. et al. The biofilm matrix scaffold of Pseudomonas aeruginosa contains G-quadruplex extracellular DNA structures. npj Biofilms Microbiomes 7, 27 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Suck, D. & Oefner, C. Structure of DNase I at 2.0 Å resolution suggests a mechanism for binding to and cutting DNA. Nature 321, 620–625 (1986).

    Article  CAS  PubMed  Google Scholar 

  22. Tetz George, V., Artemenko Natalia, K. & Tetz Victor, V. Effect of DNase and antibiotics on biofilm characteristics. Antimicrob. Agents Chemother. 53, 1204–1209 (2009).

    Article  CAS  PubMed  Google Scholar 

  23. Chen, Z. et al. A multinuclear metal complex based DNase-mimetic artificial enzyme: matrix cleavage for combating bacterial biofilms. Angew. Chem. Int. Ed. 55, 10732–10736 (2016).

    Article  CAS  Google Scholar 

  24. Hu, H. et al. A DNase-mimetic artificial enzyme for the eradication of drug-resistant bacterial biofilm infections. Nanoscale 14, 2676–2685 (2022).

    Article  CAS  PubMed  Google Scholar 

  25. Baker, P. et al. Exopolysaccharide biosynthetic glycoside hydrolases can be utilized to disrupt and prevent Pseudomonas aeruginosa biofilms. Sci. Adv. 2, e1501632 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Thorn, C. R. et al. Protective liquid crystal nanoparticles for targeted delivery of PslG: a biofilm dispersing enzyme. ACS Infect. Dis. 7, 2102–2115 (2021).

    Article  CAS  PubMed  Google Scholar 

  27. Tan, Y., Ma, S., Liu, C., Yu, W. & Han, F. Enhancing the stability and antibiofilm activity of DspB by immobilization on carboxymethyl chitosan nanoparticles. Microbiol. Res. 178, 35–41 (2015).

    Article  CAS  PubMed  Google Scholar 

  28. Izano, E. A., Amarante, M. A., Kher, W. B. & Kaplan, J. B. Differential roles of poly-N-acetylglucosamine surface polysaccharide and extracellular DNA in Staphylococcus aureus and Staphylococcus epidermidis biofilms. Appl. Environ. Microbiol. 74, 470–476 (2008).

    Article  CAS  PubMed  Google Scholar 

  29. Kerrigan, J. E. et al. Modeling and biochemical analysis of the activity of antibiofilm agent Dispersin B. Acta Biol. Hung. 59, 439–451 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Deacon, J. et al. Antimicrobial efficacy of tobramycin polymeric nanoparticles for Pseudomonas aeruginosa infections in cystic fibrosis: formulation, characterisation and functionalisation with dornase alfa (DNase). J. Control. Rel. 198, 55–61 (2015).

    Article  CAS  Google Scholar 

  31. Baelo, A. et al. Disassembling bacterial extracellular matrix with DNase-coated nanoparticles to enhance antibiotic delivery in biofilm infections. J. Control. Rel. 209, 150–158 (2015).

    Article  CAS  Google Scholar 

  32. Singh, R. et al. Affordable oral health care: dental biofilm disruption using chloroplast made enzymes with chewing gum delivery. Plant Biotechnol. J. 19, 2113–2125 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Liu, Z. et al. Functional immobilization of a biofilm-releasing glycoside hydrolase dispersin B on magnetic nanoparticles. Appl. Biochem. Biotechnol. 194, 737–747 (2022).

    Article  CAS  PubMed  Google Scholar 

  34. Pavlukhina, S. V. et al. Noneluting enzymatic antibiofilm coatings. ACS Appl. Mater. Interfaces 4, 4708–4716 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Asker, D. et al. Preventing Pseudomonas aeruginosa biofilms on indwelling catheters by surface-bound enzymes. ACS Appl. Bio Mater. 4, 8248–8258 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Sugimoto, S. et al. Staphylococcus epidermidis Esp degrades specific proteins associated with Staphylococcus aureus biofilm formation and host–pathogen interaction. J. Bacteriol. 195, 1645–1655 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Whitfield, G. B., Marmont, L. S. & Howell, P. L. Enzymatic modifications of exopolysaccharides enhance bacterial persistence. Front. Microbiol. 6, 471 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Miller, M. B. & Bassler, B. L. Quorum sensing in bacteria. Annu. Rev. Microbiol. 55, 165–199 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. Papenfort, K. & Bassler, B. L. Quorum sensing signal-response systems in Gram-negative bacteria. Nat. Rev. Microbiol. 14, 576–588 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Giaouris, E. E. & Simões, M. V. in Foodborne Diseases (eds Holban, A. M. & Grumezescu, A. M.) 309–377 (Academic Press, 2018).

  41. van Delden, C. et al. Azithromycin to prevent Pseudomonas aeruginosa ventilator-associated pneumonia by inhibition of quorum sensing: a randomized controlled trial. Intensive Care Med. 38, 1118–1125 (2012).

    Article  CAS  PubMed  Google Scholar 

  42. Ho, D.-K. et al. Squalenyl hydrogen sulfate nanoparticles for simultaneous delivery of tobramycin and an alkylquinolone quorum sensing inhibitor enable the eradication of P. aeruginosa biofilm infections. Angew. Chem. Int. Ed. 59, 10292–10296 (2020).

    Article  CAS  Google Scholar 

  43. Singh, N. et al. Dual bioresponsive antibiotic and quorum sensing inhibitor combination nanoparticles for treatment of Pseudomonas aeruginosa biofilms in vitro and ex vivo. Biomater. Sci. 7, 4099–4111 (2019).

    Article  CAS  PubMed  Google Scholar 

  44. Thompson, J. A., Oliveira, R. A., Djukovic, A., Ubeda, C. & Xavier, K. B. Manipulation of the quorum sensing signal AI-2 affects the antibiotic-treated gut microbiota. Cell Rep. 10, 1861–1871 (2015).

    Article  CAS  PubMed  Google Scholar 

  45. Krzyżek, P. Challenges and limitations of anti-quorum sensing therapies. Front. Microbiol. https://doi.org/10.3389/fmicb.2019.02473 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Imhann, F. et al. Interplay of host genetics and gut microbiota underlying the onset and clinical presentation of inflammatory bowel disease. Gut 67, 108 (2018).

    Article  CAS  PubMed  Google Scholar 

  47. Ismail, A. S., Valastyan, J. S. & Bassler, B. L. A host-produced autoinducer-2 mimic activates bacterial quorum sensing. Cell Host Microbe 19, 470–480 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Cáp, M., Váchová, L. & Palková, Z. Reactive oxygen species in the signaling and adaptation of multicellular microbial communities. Oxid. Med. Cell Longev. 2012, 976753 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Barraud, N. et al. Involvement of nitric oxide in biofilm dispersal of Pseudomonas aeruginosa. J. Bacteriol. 188, 7344–7353 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Barraud, N. et al. Nitric oxide signaling in Pseudomonas aeruginosa biofilms mediates phosphodiesterase activity, decreased cyclic di-GMP levels, and enhanced dispersal. J. Bacteriol. 191, 7333–7342 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Howlin, R. P. et al. Low-dose nitric oxide as targeted anti-biofilm adjunctive therapy to treat chronic Pseudomonas aeruginosa infection in cystic fibrosis. Mol. Ther. 25, 2104–2116 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Arce Miranda, J. E., Sotomayor, C. E., Albesa, I. & Paraje, M. G. Oxidative and nitrosative stress in Staphylococcus aureus biofilm. FEMS Microbiol. Lett. 315, 23–29 (2011).

    Article  PubMed  Google Scholar 

  53. Dwivedi, S. et al. Reactive oxygen species mediated bacterial biofilm inhibition via zinc oxide nanoparticles and their statistical determination. PLoS ONE 9, e111289 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Liu, Y. et al. Topical Ferumoxytol nanoparticles disrupt biofilms and prevent tooth decay in vivo via intrinsic catalytic activity. Nat. Commun. https://doi.org/10.1038/s41467-018-05342-x (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Liu, Y. et al. Ferumoxytol nanoparticles target biofilms causing tooth decay in the human mouth. Nano Lett. 21, 9442–9449 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Jo, Y. S. et al. Micelles for delivery of nitric oxide. J. Am. Chem. Soc. 131, 14413–14418 (2009).

    Article  CAS  PubMed  Google Scholar 

  57. Duong, H. T. et al. Nanoparticle (star polymer) delivery of nitric oxide effectively negates Pseudomonas aeruginosa biofilm formation. Biomacromolecules 15, 2583–2589 (2014).

    Article  CAS  PubMed  Google Scholar 

  58. Zhao, Z. et al. Light-triggered nitric oxide release by a photosensitizer to combat bacterial biofilm infections. Chem. Eur. J. 27, 5453–5460 (2021).

    Article  CAS  PubMed  Google Scholar 

  59. Summers, W. C. The strange history of phage therapy. Bacteriophage 2, 130–133 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Liu, D. et al. The safety and toxicity of phage therapy: a review of animal and clinical studies. Viruses https://doi.org/10.3390/v13071268 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Roach, D. R. & Debarbieux, L. Phage therapy: awakening a sleeping giant. Emerg. Top. Life Sci. 1, 93–103 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Wright, A., Hawkins, C. H., Anggård, E. E. & Harper, D. R. A controlled clinical trial of a therapeutic bacteriophage preparation in chronic otitis due to antibiotic-resistant Pseudomonas aeruginosa: a preliminary report of efficacy. Clin. Otolaryngol. 34, 349–357 (2009).

    Article  CAS  PubMed  Google Scholar 

  63. Labrie, S. J., Samson, J. E. & Moineau, S. Bacteriophage resistance mechanisms. Nat. Rev. Microbiol. 8, 317–327 (2010).

    Article  CAS  PubMed  Google Scholar 

  64. Van Belleghem, J. D., Dąbrowska, K., Vaneechoutte, M., Barr, J. J. & Bollyky, P. L. Interactions between bacteriophage, bacteria, and the mammalian immune system. Viruses https://doi.org/10.3390/v11010010 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Chadha, P., Katare, O. P. & Chhibber, S. Liposome loaded phage cocktail: enhanced therapeutic potential in resolving Klebsiella pneumoniae mediated burn wound infections. Burns 43, 1532–1543 (2017).

    Article  PubMed  Google Scholar 

  66. Otero, J. et al. Biodistribution of liposome-encapsulated bacteriophages and their transcytosis during oral phage therapy. Front. Microbiol. https://doi.org/10.3389/fmicb.2019.00689 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Colom, J. et al. Liposome-encapsulated bacteriophages for enhanced oral phage therapy against Salmonella spp. Appl. Environ. Microbiol. 81, 4841–4849 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Broekhuizen, C. A. N. et al. The influence of antibodies on Staphylococcus epidermidis adherence to polyvinylpyrrolidone-coated silicone elastomer in experimental biomaterial-associated infection in mice. Biomaterials 30, 6444–6450 (2009).

    Article  CAS  PubMed  Google Scholar 

  69. Pope, W. H. et al. Cluster K mycobacteriophages: insights into the evolutionary origins of mycobacteriophage TM4. PLoS ONE 6, e26750 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Nieth, A., Verseux, C., Barnert, S., Süss, R. & Römer, W. A first step toward liposome-mediated intracellular bacteriophage therapy. Exp. Opin. Drug Deliv. 12, 1411–1424 (2015).

    Article  Google Scholar 

  71. Vinner, G. K. & Malik, D. J. High precision microfluidic microencapsulation of bacteriophages for enteric delivery. Res. Microbiol. 169, 522–530 (2018).

    Article  CAS  PubMed  Google Scholar 

  72. González-Menéndez, E. et al. Strategies to encapsulate the Staphylococcus aureus bacteriophage phiIPLA-RODI. Viruses https://doi.org/10.3390/v10090495 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Chhibber, S., Shukla, A. & Kaur, S. Transfersomal phage cocktail is an effective treatment against methicillin-resistant Staphylococcus aureus-mediated skin and soft tissue infections. Antimicrob. Agents Chemother. 61, e02146-16 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Chang, R. Y. K., Okamoto, Y., Morales, S., Kutter, E. & Chan, H. K. Hydrogel formulations containing non-ionic polymers for topical delivery of bacteriophages. Int. J. Pharm. https://doi.org/10.1016/j.ijpharm.2021.120850 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Shen, H.-Y. et al. Controlled-release of free bacteriophage nanoparticles from 3D-plotted hydrogel fibrous structure as potential antibacterial wound dressing. J. Control. Rel. 331, 154–163 (2021).

    Article  CAS  Google Scholar 

  76. Shiue, S.-J., Syu, F.-S. & Lin, H.-Y. Two types of bacteriophage-modified alginate hydrogels as antibacterial coatings for implants. J. Taiwan Inst. Chem. Eng. 134, 104353 (2022).

    Article  CAS  Google Scholar 

  77. Barros, J. A. R. et al. Encapsulated bacteriophages in alginate-nanohydroxyapatite hydrogel as a novel delivery system to prevent orthopedic implant-associated infections. Nanomed. Nanotechnol. Biol. Med. 24, 102145 (2020).

    Article  CAS  Google Scholar 

  78. Malik, D. J. et al. Formulation, stabilisation and encapsulation of bacteriophage for phage therapy. Adv. Colloid Interface Sci. 249, 100–133 (2017).

    Article  CAS  PubMed  Google Scholar 

  79. Ma, Y. et al. Microencapsulation of bacteriophage felix O1 into chitosan-alginate microspheres for oral delivery. Appl. Environ. Microbiol. 74, 4799–4805 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Wroe, J. A., Johnson, C. T. & García, A. J. Bacteriophage delivering hydrogels reduce biofilm formation in vitro and infection in vivo. J. Biomed. Mater. Res. A 108, 39–49 (2020).

    Article  CAS  PubMed  Google Scholar 

  81. Rajora, M. A., Lou, J. W. H. & Zheng, G. Advancing porphyrin’s biomedical utility via supramolecular chemistry. Chem. Soc. Rev. 46, 6433–6469 (2017).

    Article  CAS  PubMed  Google Scholar 

  82. Ordonez, A. A., Bambarger, L. E., Jain, S. K. & Weinstein, E. A. in Imaging Infections: From Bench to Bedside (ed. Jain, S. K.) 209–222 (Springer International Publishing, 2017).

  83. Wollmer, P. et al. Measurement of pulmonary erythromycin concentration in patients with lobar pneumonia by means of positron tomography. Lancet 320, 1361–1364 (1982).

    Article  Google Scholar 

  84. Kuroda, K., Caputo, G. A. & DeGrado, W. F. The role of hydrophobicity in the antimicrobial and hemolytic activities of polymethacrylate derivatives. Chemistry 15, 1123–1133 (2009).

    Article  CAS  PubMed  Google Scholar 

  85. Ghobrial, O., Derendorf, H. & Hillman, J. D. Human serum binding and its effect on the pharmacodynamics of the lantibiotic MU1140. Eur. J. Pharm. Sci. 41, 658–664 (2010).

    Article  CAS  PubMed  Google Scholar 

  86. He, J., Abdelraouf, K., Ledesma, K. R., Chow, D. S. & Tam, V. H. Pharmacokinetics and efficacy of liposomal polymyxin B in a murine pneumonia model. Int. J. Antimicrob. Agents 42, 559–564 (2013).

    Article  CAS  PubMed  Google Scholar 

  87. Li, C. et al. Preparation and characterization of flexible nanoliposomes loaded with daptomycin, a novel antibiotic, for topical skin therapy. Int. J. Nanomed. 8, 1285–1292 (2013).

    Article  Google Scholar 

  88. Veloso, D. et al. Intravenous delivery of a liposomal formulation of voriconazole improves drug pharmacokinetics, tissue distribution, and enhances antifungal activity. Drug Deliv. 25, 1585–1594 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Marier, J. F., Lavigne, J. & Ducharme, M. P. Pharmacokinetics and efficacies of liposomal and conventional formulations of tobramycin after intratracheal administration in rats with pulmonary Burkholderia cepacia infection. Antimicrob. Agents Chemother. 46, 3776–3781 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Liao, F.-H. et al. A supramolecular trap to increase the antibacterial activity of colistin. Angew. Chem. Int. Ed. 59, 1430–1434 (2020).

    Article  CAS  Google Scholar 

  91. Ramalingam, B., Parandhaman, T. & Das, S. K. Antibacterial effects of biosynthesized silver nanoparticles on surface ultrastructure and nanomechanical properties of Gram-negative bacteria viz. Escherichia coli and Pseudomonas aeruginosa. ACS Appl. Mater. Interfaces 8, 4963–4976 (2016).

    Article  CAS  PubMed  Google Scholar 

  92. Vinoj, G., Pati, R., Sonawane, A. & Vaseeharan, B. In vitro cytotoxic effects of gold nanoparticles coated with functional acyl homoserine lactone lactonase protein from Bacillus licheniformis and their antibiofilm activity against Proteus species. Antimicrob. Agents Chemother. 59, 763–771 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  93. McShan, D., Zhang, Y., Deng, H., Ray, P. C. & Yu, H. Synergistic antibacterial effect of silver nanoparticles combined with ineffective antibiotics on drug resistant Salmonella typhimurium DT104. J. Environ. Sci. Health Part C 33, 369–384 (2015).

    Article  CAS  Google Scholar 

  94. Brar, A. et al. Nanoparticle-enabled combination therapy showed superior activity against multi-drug resistant bacterial pathogens in comparison to free drugs. Nanomaterials https://doi.org/10.3390/nano12132179 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Abed, N. et al. An efficient system for intracellular delivery of beta-lactam antibiotics to overcome bacterial resistance. Sci. Rep. 5, 13500 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Pace, L. R., Harrison, Z. L., Brown, M. N., Haggard, W. O. & Amber Jennings, J. Characterization and antibiofilm activity of mannitol–chitosan-blended paste for local antibiotic delivery system. Mar. Drugs https://doi.org/10.3390/md17090517 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Stine, A. E. et al. Modeling the response of a biofilm to silver-based antimicrobial. Math. Biosci. 244, 29–39 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Zhang, S. et al. Insights of metallic nanoparticles and ions in accelerating the bacterial uptake of antibiotic resistance genes. J. Hazard. Mater. 421, 126728 (2022).

    Article  CAS  PubMed  Google Scholar 

  99. Uhl, P. et al. Oral delivery of vancomycin by tetraether lipid liposomes. Eur. J. Pharm. Sci. 108, 111–118 (2017).

    Article  CAS  PubMed  Google Scholar 

  100. Li, X. et al. Control of nanoparticle penetration into biofilms through surface design. Chem. Commun. 51, 282–285 (2015).

    Article  CAS  Google Scholar 

  101. Hayden, S. C. et al. Aggregation and interaction of cationic nanoparticles on bacterial surfaces. J. Am. Chem. Soc. 134, 6920–6923 (2012).

    Article  CAS  PubMed  Google Scholar 

  102. Ding, X. et al. Antibacterial and antifouling catheter coatings using surface grafted PEG-b-cationic polycarbonate diblock copolymers. Biomaterials 33, 6593–6603 (2012).

    Article  CAS  PubMed  Google Scholar 

  103. Liu, Y. et al. Surface-adaptive, antimicrobially loaded, micellar nanocarriers with enhanced penetration and killing efficiency in Staphylococcal biofilms. ACS Nano 10, 4779–4789 (2016).

    Article  CAS  PubMed  Google Scholar 

  104. Hu, D., Deng, Y., Jia, F., Jin, Q. & Ji, J. Surface charge switchable supramolecular nanocarriers for nitric oxide synergistic photodynamic eradication of biofilms. ACS Nano 14, 347–359 (2020).

    Article  CAS  PubMed  Google Scholar 

  105. Vuong, C. et al. Polysaccharide intercellular adhesin (PIA) protects Staphylococcus epidermidis against major components of the human innate immune system. Cell. Microbiol. 6, 269–275 (2004).

    Article  CAS  PubMed  Google Scholar 

  106. Peulen, T.-O. & Wilkinson, K. J. Diffusion of nanoparticles in a biofilm. Environ. Sci. Technol. 45, 3367–3373 (2011).

    Article  CAS  PubMed  Google Scholar 

  107. Forier, K. et al. Probing the size limit for nanomedicine penetration into Burkholderia multivorans and Pseudomonas aeruginosa biofilms. J. Control. Rel. 195, 21–28 (2014).

    Article  CAS  Google Scholar 

  108. Xie, Y., Yang, J., Zhang, J., Zheng, W. & Jiang, X. Activating the antibacterial effect of 4,6-diamino-2-pyrimidinethiol-modified gold nanoparticles by reducing their sizes. Angew. Chem. Int. Ed. 59, 23471–23475 (2020).

    Article  CAS  Google Scholar 

  109. Chen, M. et al. Bacterial biofilm destruction by size/surface charge-adaptive micelles. Nanoscale 11, 1410–1422 (2019).

    Article  CAS  PubMed  Google Scholar 

  110. Ahmed, K., Muiruri, P. W., Jones, G. H., Scott, M. J. & Jones, M. N. The effect of grafted poly (ethylene glycol) on the electrophoretic properties of phospholipid liposomes and their adsorption to bacterial biofilms. Colloids Surf. A Physicochem. Eng. Asp. 194, 287–296 (2001).

    Article  CAS  Google Scholar 

  111. Moghadas-Sharif, N., Fazly Bazzaz, B. S., Khameneh, B. & Malaekeh-Nikouei, B. The effect of nanoliposomal formulations on Staphylococcus epidermidis biofilm. Drug Dev. Ind. Pharm. 41, 445–450 (2015).

    Article  CAS  PubMed  Google Scholar 

  112. Aiello, S. et al. Mannosyl, glucosyl or galactosyl liposomes to improve resveratrol efficacy against methicillin resistant Staphylococcus aureus biofilm. Colloids Surf. A Physicochem. Eng. Asp. 617, 126321 (2021).

    Article  CAS  Google Scholar 

  113. Beaulac, C., Sachetelli, S. & Lagace, J. In-vitro bactericidal efficacy of sub-MIC concentrations of liposome-encapsulated antibiotic against Gram-negative and Gram-positive bacteria. J. Antimicrob. Chemother. 41, 35–41 (1998).

    Article  CAS  PubMed  Google Scholar 

  114. Beaulac, C., Sachetelli, S. & Lagacé, J. Aerosolization of low phase transition temperature liposomal tobramycin as a dry powder in an animal model of chronic pulmonary infection caused by Pseudomonas aeruginosa. J. Drug Target. 7, 33–41 (1999).

    Article  CAS  PubMed  Google Scholar 

  115. Scriboni, A. B. et al. Fusogenic liposomes increase the antimicrobial activity of vancomycin against Staphylococcus aureus biofilm. Front. Pharmacol. 10, 1401 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Takeda, S. et al. Protection against endocarditis due to Staphylococcus epidermidis by immunization with capsular polysaccharide/adhesin. Circulation 84, 2539–2546 (1991).

    Article  CAS  PubMed  Google Scholar 

  117. Kelly-Quintos, C., Cavacini, L. A., Posner, M. R., Goldmann, D. & Pier, G. B. Characterization of the opsonic and protective activity against Staphylococcus aureus of fully human monoclonal antibodies specific for the bacterial surface polysaccharide poly-N-acetylglucosamine. Infect. Immun. 74, 2742–2750 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Le, H. et al. Antibody-conjugated nanocarriers for targeted antibiotic delivery: application in the treatment of bacterial biofilms. Biomacromolecules 22, 1639–1653 (2021).

    Article  CAS  PubMed  Google Scholar 

  119. França, A., Vilanova, M., Cerca, N. & Pier, G. B. Monoclonal antibody raised against PNAG has variable effects on static S. epidermidis biofilm accumulation in vitro. Int. J. Biol. Sci. 9, 518–520 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  120. DiGiandomenico, A. et al. Identification of broadly protective human antibodies to Pseudomonas aeruginosa exopolysaccharide Psl by phenotypic screening. J. Exp. Med. 209, 1273–1287 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Robinson, A. M., Creeth, J. E. & Jones, M. N. The specificity and affinity of immunoliposome targeting to oral bacteria. Biochim. Biophys. Acta 1369, 278–286 (1998).

    Article  CAS  PubMed  Google Scholar 

  122. Novotny, L. A., Jurcisek, J. A., Goodman, S. D. & Bakaletz, L. O. Monoclonal antibodies against DNA-binding tips of DNABII proteins disrupt biofilms in vitro and induce bacterial clearance in vivo. eBioMedicine 10, 33–44 (2016).

    CAS  Google Scholar 

  123. Estellés, A. et al. A high-affinity native human antibody disrupts biofilm from Staphylococcus aureus bacteria and potentiates antibiotic efficacy in a mouse implant infection model. Antimicrob. Agents Chemother. 60, 2292–2301 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  124. Keefe, A. D., Pai, S. & Ellington, A. Aptamers as therapeutics. Nat. Rev. Drug Discov. 9, 537–550 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Ommen, P. et al. Aptamer-targeted drug delivery for Staphylococcus aureus biofilm. Front. Cell Infect. Microbiol. 12, 814340 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Wang, S., Mao, B., Wu, M., Liang, J. & Deng, L. Influence of aptamer-targeted antibiofilm agents for treatment of Pseudomonas aeruginosa biofilms. Antonie van Leeuwenhoek 111, 199–208 (2018).

    Article  CAS  PubMed  Google Scholar 

  127. Yuan, Z. et al. Remote eradication of biofilm on titanium implant via near-infrared light triggered photothermal/photodynamic therapy strategy. Biomaterials https://doi.org/10.1016/j.biomaterials.2019.119479 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Ghosh, S. et al. Loading and releasing ciprofloxacin in photoactivatable liposomes. Biochem. Eng. J. 141, 43–48 (2019).

    Article  CAS  PubMed  Google Scholar 

  129. Grzech-Leśniak, K., Gaspirc, B. & Sculean, A. Clinical and microbiological effects of multiple applications of antibacterial photodynamic therapy in periodontal maintenance patients. A randomized controlled clinical study. Photodiagn. Photodyn. Ther. 27, 44–50 (2019).

    Article  Google Scholar 

  130. Lulic, M. et al. One-year outcomes of repeated adjunctive photodynamic therapy during periodontal maintenance: a proof-of-principle randomized-controlled clinical trial. J. Clin. Periodontol. 36, 661–666 (2009).

    Article  PubMed  Google Scholar 

  131. Salvi, G. E. et al. Adjunctive laser or antimicrobial photodynamic therapy to non-surgical mechanical instrumentation in patients with untreated periodontitis: a systematic review and meta-analysis. J. Clin. Periodontol. 47, 176–198 (2020).

    Article  PubMed  Google Scholar 

  132. Lattwein, K. R. et al. Sonobactericide: an emerging treatment strategy for bacterial infections. Ultrasound Med. Biol. 46, 193–215 (2020).

    Article  PubMed  Google Scholar 

  133. Horsley, H. et al. Ultrasound-activated microbubbles as a novel intracellular drug delivery system for urinary tract infection. J. Control. Rel. 301, 166–175 (2019).

    Article  CAS  Google Scholar 

  134. Attinger, C. & Wolcott, R. Clinically addressing biofilm in chronic wounds. Adv. Wound Care 1, 127–132 (2012).

    Article  Google Scholar 

  135. Li, Y., Liu, G., Wang, X., Hu, J. & Liu, S. Enzyme-responsive polymeric vesicles for bacterial-strain-selective delivery of antimicrobial agents. Angew. Chem. Int. Ed. 55, 1760–1764 (2016).

    Article  CAS  Google Scholar 

  136. Zhou, J. et al. Characterization and optimization of pH-responsive polymer nanoparticles for drug delivery to oral biofilms. J. Mater. Chem. B 4, 3075–3085 (2016).

    Article  CAS  PubMed  Google Scholar 

  137. Naha, P. C. et al. Dextran-coated iron oxide nanoparticles as biomimetic catalysts for localized and pH-activated biofilm disruption. ACS Nano 13, 4960–4971 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Chua, S. L. et al. Dispersed cells represent a distinct stage in the transition from bacterial biofilm to planktonic lifestyles. Nat. Commun. 5, 4462 (2014).

    Article  CAS  PubMed  Google Scholar 

  139. Fleming, D. & Rumbaugh, K. The consequences of biofilm dispersal on the host. Sci. Rep. 8, 10738 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Bieber, D. et al. Type IV pili, transient bacterial aggregates, and virulence of enteropathogenic Escherichia coli. 280, 2114-2118 (1998).

  141. Høiby, N. et al. ESCMID guideline for the diagnosis and treatment of biofilm infections 2014. Clin. Microbiol. Infect. 21, S1–S25 (2015).

    Article  PubMed  Google Scholar 

  142. Stewart, P. S. & Franklin, M. J. Physiological heterogeneity in biofilms. Nat. Rev. Microbiol. 6, 199–210 (2008).

    Article  CAS  PubMed  Google Scholar 

  143. Karygianni, L., Ren, Z., Koo, H. & Thurnheer, T. Biofilm matrixome: extracellular components in structured microbial communities. Trends Microbiol. 28, 668–681 (2020).

    Article  CAS  PubMed  Google Scholar 

  144. Lourenço, A. et al. Minimum information about a biofilm experiment (MIABiE): standards for reporting experiments and data on sessile microbial communities living at interfaces. Pathog. Dis. 70, 250–256 (2014).

    Article  PubMed  Google Scholar 

  145. Shi, L. et al. Limits of propidium iodide as a cell viability indicator for environmental bacteria. Cytom. A 71, 592–598 (2007).

    Article  Google Scholar 

  146. Yang, J. et al. Does the gut microbiota modulate host physiology through polymicrobial biofilms? Microbes Environ. https://doi.org/10.1264/jsme2.ME20037 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Dejea, C. M. et al. Microbiota organization is a distinct feature of proximal colorectal cancers. Proc. Natl Acad. Sci. USA 111, 18321–18326 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Raza, S., Matuła, K., Karoń, S. & Paczesny, J. Resistance and adaptation of bacteria to non-antibiotic antibacterial agents: physical stressors, nanoparticles, and bacteriophages. Antibiotics https://doi.org/10.3390/antibiotics10040435 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  149. Craigen, B., Dashiff, A. & Kadouri, D. E. The use of commercially available alpha-amylase compounds to inhibit and remove Staphylococcus aureus biofilms. Open Microbiol. J. 5, 21–31 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Chemani, C. et al. Role of LecA and LecB lectins in Pseudomonas aeruginosa-induced lung injury and effect of carbohydrate ligands. Infect. Immun. 77, 2065–2075 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. van Tilburg Bernardes, E., Charron-Mazenod, L., Reading David, J., Reckseidler-Zenteno Shauna, L. & Lewenza, S. Exopolysaccharide-repressing small molecules with antibiofilm and antivirulence activity against Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 61, e01997-16 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  152. Loughran, A. J. et al. Impact of individual extracellular proteases on Staphylococcus aureus biofilm formation in diverse clinical isolates and their isogenic sarA mutants. Microbiologyopen 3, 897–909 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Cescutti, P. et al. First report of a lyase for cepacian, the polysaccharide produced by Burkholderia cepacia complex bacteria. Biochem. Biophys. Res. Commun. 339, 821–826 (2006).

    Article  CAS  PubMed  Google Scholar 

  154. Martinez, L. R. et al. Demonstration of antibiofilm and antifungal efficacy of chitosan against candidal biofilms, using an in vivo central venous catheter model. J. Infect. Dis. 201, 1436–1440 (2010).

    Article  CAS  PubMed  Google Scholar 

  155. Hayacibara, M. F. et al. The influence of mutanase and dextranase on the production and structure of glucans synthesized by streptococcal glucosyltransferases. Carbohydr. Res. 339, 2127–2137 (2004).

    Article  CAS  PubMed  Google Scholar 

  156. Gawande, P. V., Leung, K. P. & Madhyastha, S. Antibiofilm and antimicrobial efficacy of DispersinB®-KSL-W peptide-based wound gel against chronic wound infection associated bacteria. Curr. Microbiol. 68, 635–641 (2014).

    Article  CAS  PubMed  Google Scholar 

  157. Yang, C. & Montgomery, M. Dornase alfa for cystic fibrosis. Cochrane Database Syst. Rev. https://doi.org/10.1002/14651858.CD001127.pub5 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  158. Hwang, G. et al. Candida albicans mannans mediate Streptococcus mutans exoenzyme GtfB binding to modulate cross-kingdom biofilm development in vivo. PLoS Pathog. 13, e1006407 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  159. Ibrahim, A. M., Hamouda, R. A., El-Naggar, N. E. & Al-Shakankery, F. M. Bioprocess development for enhanced endoglucanase production by newly isolated bacteria, purification, characterization and in-vitro efficacy as anti-biofilm of Pseudomonas aeruginosa. Sci. Rep. 11, 9754 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Iwase, T. et al. Staphylococcus epidermidis Esp inhibits Staphylococcus aureus biofilm formation and nasal colonization. Nature 465, 346–349 (2010).

    Article  CAS  PubMed  Google Scholar 

  161. Trizna, E. et al. Improving the efficacy of antimicrobials against biofilm-embedded bacteria using bovine hyaluronidase azoximer (Longidaza®). Pharmaceutics 13, 1740 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Boyd, C. D., Chatterjee, D., Sondermann, H. & O’Toole, G. A. LapG, required for modulating biofilm formation by Pseudomonas fluorescens Pf0-1, is a calcium-dependent protease. J. Bacteriol. 194, 4406–4414 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Yuan, S. et al. Lysozyme-coupled poly(poly(ethylene glycol) methacrylate)−stainless steel hybrids and their antifouling and antibacterial surfaces. Langmuir 27, 2761–2774 (2011).

    Article  CAS  PubMed  Google Scholar 

  164. Eladawy, M., El-Mowafy, M., El-Sokkary, M. M. A. & Barwa, R. Effects of lysozyme, proteinase K, and cephalosporins on biofilm formation by clinical isolates of Pseudomonas aeruginosa. Interdiscip. Perspect. Infect. Dis. 2020, 6156720 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  165. Passariello, C., Lucchese, A., Pera, F. & Gigola, P. Clinical, microbiological and inflammatory evidence of the efficacy of combination therapy including serratiopeptidase in the treatment of periimplantitis. Eur. J. Inflamm. 10, 463–472 (2012).

    Article  CAS  Google Scholar 

  166. Liu, J., Madec, J.-Y., Bousquet-Mélou, A., Haenni, M. & Ferran, A. A. Destruction of Staphylococcus aureus biofilms by combining an antibiotic with subtilisin A or calcium gluconate. Sci. Rep. 11, 6225 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Ivanova, K. et al. Quorum-quenching and matrix-degrading enzymes in multilayer coatings synergistically prevent bacterial biofilm formation on urinary catheters. ACS Appl. Mater. Interfaces 7, 27066–27077 (2015).

    Article  CAS  PubMed  Google Scholar 

  168. Deng, Y. et al. Diffusible signal factor (DSF) quorum sensing signal and structurally related molecules enhance the antimicrobial efficacy of antibiotics against some bacterial pathogens. BMC Microbiol. 14, 51 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  169. Marques, C. N., Davies, D. G. & Sauer, K. Control of biofilms with the fatty acid signaling molecule cis-2-decenoic acid. Pharmaceuticals 8, 816–835 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Nagy, F. et al. In vitro and in vivo effect of exogenous farnesol exposure against Candida auris. Front. Microbiol. 11, 957 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  171. Gómez, A.-C. et al. Synthesis and evaluation of novel furanones as biofilm inhibitors in opportunistic human pathogens. Eur. J. Med. Chem. 242, 114678 (2022).

    Article  PubMed  Google Scholar 

  172. Raychaudhuri, S., Jain, V. & Dongre, M. Identification of a constitutively active variant of LuxO that affects production of HA/protease and biofilm development in a non-O1, non-O139 Vibrio cholerae O110. Gene 369, 126–133 (2006).

    Article  CAS  PubMed  Google Scholar 

  173. Hraiech, S. et al. Inhaled lactonase reduces Pseudomonas aeruginosa quorum sensing and mortality in rat pneumonia. PLoS ONE 9, e107125 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  174. Weiland-Bräuer, N., Kisch, M. J., Pinnow, N., Liese, A. & Schmitz, R. A. Highly effective inhibition of biofilm formation by the first metagenome-derived AI-2 quenching enzyme. Front. Microbiol. 7, 1098 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  175. Simonetti, O. et al. Efficacy of the quorum sensing inhibitor fs10 alone and in combination with tigecycline in an animal model of Staphylococcal infected wound. PLoS ONE 11, e0151956 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  176. Sully, E. K. et al. Selective chemical inhibition of agr quorum sensing in Staphylococcus aureus promotes host defense with minimal impact on resistance. PLoS Pathog. 10, e1004174 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  177. Baldry, M. et al. The agr inhibitors solonamide B and analogues alter immune responses to Staphylococccus aureus but do not exhibit adverse effects on immune cell functions. PLoS ONE 11, e0145618 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  178. Anderson, A. C. et al. In-vivo shift of the microbiota in oral biofilm in response to frequent sucrose consumption. Sci. Rep. 8, 14202 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  179. Hassanov, T., Karunker, I., Steinberg, N., Erez, A. & Kolodkin-Gal, I. Novel antibiofilm chemotherapies target nitrogen from glutamate and glutamine. Sci. Rep. 8, 7097 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  180. Mishra, B. et al. Design and evaluation of short bovine lactoferrin-derived antimicrobial peptides against multidrug-resistant Enterococcus faecium. Antibiotics https://doi.org/10.3390/antibiotics11081085 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  181. Deppisch, C. et al. Gaseous nitric oxide to treat antibiotic resistant bacterial and fungal lung infections in patients with cystic fibrosis: a phase I clinical study. Infection 44, 513–520 (2016).

    Article  CAS  PubMed  Google Scholar 

  182. Kolpen, M. et al. Hyperbaric oxygen sensitizes anoxic Pseudomonas aeruginosa biofilm to ciprofloxacin. Antimicrob. Agents Chemother. https://doi.org/10.1128/aac.01024-17 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  183. Lei, X. et al. Degradable microneedle patches loaded with antibacterial gelatin nanoparticles to treat staphylococcal infection-induced chronic wounds. Int. J. Biol. Macromol. 217, 55–65 (2022).

    Article  CAS  PubMed  Google Scholar 

  184. Song, Y. et al. Cationic and anionic antimicrobial agents co-templated mesostructured silica nanocomposites with a spiky nanotopology and enhanced biofilm inhibition performance. Nanomicro Lett. https://doi.org/10.1007/s40820-022-00826-4 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  185. Pourhajibagher, M., Keshavarz Valian, N. & Bahador, A. Theranostic nanoplatforms of Emodin-chitosan with blue laser light on enhancing the anti-biofilm activity of photodynamic therapy against Streptococcus mutans biofilms on the enamel surface. BMC Microbiol. 22, 68 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Xiu, W. et al. Potentiating hypoxic microenvironment for antibiotic activation by photodynamic therapy to combat bacterial biofilm infections. Nat. Commun. 13, 3875 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Pourhajibagher, M., Pourakbari, B. & Bahador, A. Contribution of antimicrobial photo-sonodynamic therapy in wound healing: an in vivo effect of curcumin-nisin-based poly (l-lactic acid) nanoparticle on Acinetobacter baumannii biofilms. BMC Microbiol. 22, 28 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Blanco-Cabra, N. et al. Neutralization of ionic interactions by dextran-based single-chain nanoparticles improves tobramycin diffusion into a mature biofilm. npj Biofilms Microbiomes 8, 52 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Hu, J. et al. Surface modification of titanium substrate via combining photothermal therapy and quorum-sensing-inhibition strategy for improving osseointegration and treating biofilm-associated bacterial infection. Bioact. Mater. 18, 228–241 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Nosrati, M. & Ranjbar, R. Investigation of the antibacterial and biofilm inhibitory activities of Prangos acaulis (DC.) Bornm in nanoparticulated formulation. Nanotechnology 33, 385103 (2022).

    Article  Google Scholar 

  191. Xu, Y. et al. Dental plaque-inspired versatile nanosystem for caries prevention and tooth restoration. Bioact. Mater. 20, 418–433 (2023).

    Article  CAS  PubMed  Google Scholar 

  192. Nie, B. et al. Bone infection site targeting nanoparticle-antibiotics delivery vehicle to enhance treatment efficacy of orthopedic implant related infection. Bioact. Mater. 16, 134–148 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Wang, L. et al. pH and lipase-responsive nanocarrier-mediated dual drug delivery system to treat periodontitis in diabetic rats. Bioact. Mater. 18, 254–266 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Pourhajibagher, M. & Bahador, A. Aptamer decorated Emodin nanoparticles-assisted delivery of dermcidin-derived peptide DCD-1L: photoactive bio-theragnostic agent for Enterococcus faecalis biofilm destruction. Photodiagn. Photodyn. Ther. 39, 103020 (2022).

    Article  CAS  Google Scholar 

  195. Wang, Y. et al. A novel antibacterial and antifouling nanocomposite coated endotracheal tube to prevent ventilator-associated pneumonia. J. Nanobiotechnol. 20, 112 (2022).

    Article  CAS  Google Scholar 

  196. Zhang, Y. et al. pH-responsive hierarchical H2S-releasing nano-disinfectant with deep-penetrating and anti-inflammatory properties for synergistically enhanced eradication of bacterial biofilms and wound infection. J. Nanobiotechnol. 20, 55 (2022).

    Article  Google Scholar 

  197. Eivazzadeh-Keihan, R. et al. A novel, bioactive and antibacterial scaffold based on functionalized graphene oxide with lignin, silk fibroin and ZnO nanoparticles. Sci. Rep. 12, 8770 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Ding, M., Zhao, W., Zhang, X., Song, L. & Luan, S. Charge-switchable MOF nanocomplex for enhanced biofilm penetration and eradication. J. Hazard. Mater. 439, 129594 (2022).

    Article  CAS  PubMed  Google Scholar 

  199. Zhang, Y. et al. Bacterial biofilm microenvironment responsive copper-doped zinc peroxide nanocomposites for enhancing chemodynamic therapy. Chem. Eng. J. 446, 137214 (2022).

    Article  CAS  Google Scholar 

  200. Tarawneh, O. et al. Assessment of persistent antimicrobial and anti-biofilm activity of p-HEMA hydrogel loaded with rifampicin and cefixime. Sci. Rep. 12, 3900 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Schiavi, D., Francesconi, S., Taddei, A. R., Fortunati, E. & Balestra, G. M. Exploring cellulose nanocrystals obtained from olive tree wastes as sustainable crop protection tool against bacterial diseases. Sci. Rep. 12, 6149 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Abraham, W. L. et al. Biofilm inhibition and bacterial eradication by C-dots derived from polyethyleneimine-citric acid. Colloids Surf. B Biointerfaces 217, 112704 (2022).

    Article  CAS  Google Scholar 

  203. Yang, C. et al. EGCG-coated silver nanoparticles self-assemble with selenium nanowires for treatment of drug-resistant bacterial infections by generating ROS and disrupting biofilms. Nanotechnology 33, 415101 (2022).

    Article  Google Scholar 

  204. Tang, S. et al. Fucoidan-derived carbon dots against Enterococcus faecalis biofilm and infected dentinal tubules for the treatment of persistent endodontic infections. J. Nanobiotechnol. 20, 321 (2022).

    Article  CAS  Google Scholar 

  205. Wang, L., Liu, L., Liu, Y., Wang, F. & Zhou, X. Antimicrobial performance of novel glutathione-conjugated silver nanoclusters (GSH@AgNCs) against Escherichia coli and Staphylococcus aureus by membrane-damage and biofilm-inhibition mechanisms. Food Res. Int. 160, 111680 (2022).

    Article  CAS  PubMed  Google Scholar 

  206. Piri-Gharaghie, T. et al. Effects of imipenem-containing niosome nanoparticles against high prevalence methicillin-resistant Staphylococcus epidermidis biofilm formed. Sci. Rep. 12, 5140 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Etemad-Moghadam, S., Alaeddini, M., Mousavi, R. & Bahador, A. DNA-aptamer-nanographene oxide as a targeted bio-theragnostic system in antimicrobial photodynamic therapy against Porphyromonas gingivalis. Sci. Rep. 12, 12161 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  208. Hsu, Y.-J. et al. Self-redox reaction driven in situ formation of Cu2O/Ti3C2Tx nanosheets boost the photocatalytic eradication of multi-drug resistant bacteria from infected wound. J. Nanobiotechnol. 20, 235 (2022).

    Article  CAS  Google Scholar 

  209. Weng, L. et al. Lactobacillus cell envelope-coated nanoparticles for antibiotic delivery against cariogenic biofilm and dental caries. J. Nanobiotechnol. 20, 356 (2022).

    Article  CAS  Google Scholar 

  210. Eskikaya, O. et al. Synthesis of two different zinc oxide nanoflowers and comparison of antioxidant and photocatalytic activity. Chemosphere 306, 135389 (2022).

    Article  CAS  PubMed  Google Scholar 

  211. Meng, F. et al. Nanocluster-mediated photothermia improves eradication efficiency and antibiotic sensitivity of Helicobacter pylori. Cancer Nanotechnol. 13, 13 (2022).

    Article  CAS  Google Scholar 

  212. Kolpen, M. et al. Bacterial biofilms predominate in both acute and chronic human lung infections. Thorax 77, 1015 (2022).

    Article  PubMed  Google Scholar 

  213. Reid, G. et al. Bacterial biofilm formation in the urinary bladder of spinal cord injured patients. Paraplegia 30, 711–717 (1992).

    CAS  PubMed  Google Scholar 

  214. Staats, A., Li, D., Sullivan, A. C. & Stoodley, P. Biofilm formation in periprosthetic joint infections. Ann. Jt. https://doi.org/10.21037/aoj-20-85 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  215. James, G. A. et al. Biofilms in chronic wounds. Wound Repair. Regen. 16, 37–44 (2008).

    Article  PubMed  Google Scholar 

  216. Oliva, A. et al. Detection of biofilm-associated implant pathogens in cardiac device infections: high sensitivity of sonication fluid culture even in the presence of antimicrobials. J. Glob. Infect. Dis. 10, 74–79 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Passerini, L., Lam, K., Costerton, J. W. & King, E. G. Biofilms on indwelling vascular catheters. Crit. Care Med. 20, 665–673 (1992).

    Article  CAS  PubMed  Google Scholar 

  218. Banu, A., Hassan, M., Rajkumar, J. & Srinivasa, S. Spectrum of bacteria associated with diabetic foot ulcer and biofilm formation: a prospective study. Aust. Med. J. 8, 280–285 (2015).

    Article  Google Scholar 

  219. von Rosenvinge, E. C., O’May, G. A., Macfarlane, S., Macfarlane, G. T. & Shirtliff, M. E. Microbial biofilms and gastrointestinal diseases. Pathog. Dis. 67, 25–38 (2013).

    Article  Google Scholar 

Download references

Acknowledgements

The authors acknowledge their funding sources: the Engineering and Physical Sciences Research Council (EP/V026623/1).

Author information

Authors and Affiliations

Authors

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Eleanor Stride.

Ethics declarations

Competing interests

E.S. and J.L.R. are named inventors on a patent application for a microparticulate formulation of antibiotics for urinary tract infection treatment; this formulation, however, is not promoted in this Review. V.C., P.S. and D.C. do not declare any competing interests.

Peer review

Peer review information

Nature Reviews Microbiology thanks Oana Ciofu, Saji George and Kendra Rumbaugh for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Biofilms

Dynamic self-constructed accumulations of microorganisms producing a matrix of extracellular biopolymers (extracellular polysaccharides).

Persister

A phenotypical survival strategy used by small populations of cells within the larger population that enter a state of dormancy and are thus protected from antibiotics functioning by disrupting metabolic activity or other growth processes. Persister cells can form in response to conditions of extreme stress or even under optimal growth and nutrient conditions. Persister cells are thought to resuscitate in vivo or upon culture in laboratory conditions when the antimicrobial is removed, differentiating them from viable-but-nonculturable cells, although there is still debate on the definitions of these phenotypes.

Reactive nitrosyl species

RNS. Derivative radicals formed by the reduction of molecular nitrogen. Examples include nitric oxide (NO), peroxynitrite (ONOO) and nitrous acid (HNO2).

Reactive oxygen species

Derivative radicals formed by the reduction of molecular oxygen. Examples include superoxide (O2), hydrogen peroxide (H2O2), hypochlorous acid (HClO) and hydroxyl radicals (-HO).

Resistance

Acquired or intrinsic genetic mutations permitting growth of microorganisms in the presence of bactericidal (or bacteriostatic) agents (minimum inhibitory concentration above breakpoint) through mechanisms such as efflux pumps, enzymatic drug inactivation or modifications in drug targets.

Supramolecular assemblies

A complex of molecules held together by usually non-covalent bonds, usually through stoichiometrically interacting particles or in large complexes. This can include quaternary protein structures such as DNA, biological membranes and synthetic compounds such as most drug or peptide-loaded nanomaterials.

Tolerance

The ability to survive, but not grow, in the presence of bactericidal agents; for example, via reduced growth rate or survival of dormant persister cells.

Viable-but-nonculturable

(VBNC). Cells that survive and grow in vivo but are not capable of growing or dividing by conventional laboratory methods. This can be due to reduced metabolic activity as a survival strategy in response to conditions of extreme stress or inappropriate culture conditions not reflecting essential growth requirements of the in vivo environment. VBNCs have been reported as being antibiotic, heavy metal, temperature, pH and biocidal-tolerant. In this case, some VBNCs are thought to resuscitate under specific conditions and/or with time once the stressor is removed.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Choi, V., Rohn, J.L., Stoodley, P. et al. Drug delivery strategies for antibiofilm therapy. Nat Rev Microbiol 21, 555–572 (2023). https://doi.org/10.1038/s41579-023-00905-2

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41579-023-00905-2

This article is cited by

Search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research