To a large extent, the dense extracellular matrix (ECM), which tightly connects tumor cells to arm the tumor into an intractable fortress, significantly decreases the nanoparticles delivery efficacy and overall performance in cancer treatments. Therefore, it is necessary to transform the dense stroma of solid tumors to loose state, which could realize deep penetration of nanomedicine and enhance cancer treatment effects. Here, we fabricated a protein-free collagen nanosweeper, triphenylphosphonium bromide (TPP) coated and S-nitrosothiols loaded mini-sized Au@silica nanorod (Au@SiO₂-SNO/PEG/TPP, GSNP-TPP), to clear the transport barriers of nanoparticles as well as elevate enhanced permeability and retention (EPR) effect, thus alleviating the diffusion resistance and realizing further penetration of nanoparticles./nMethods: By modifying the Au@silica with thermo-sensitive S-nitrosothiols, the carrier could release the nitric oxide (NO) due to the surface overheat as well as perform photothermal therapy (PTT) under near-infrared (NIR) laser irradiation. The level of collagen depletion was observed via western blotting and immunofluorescent staining. In addition, the dual-imaging and antitumor efficiency of GSNP-TPPs were evaluated with the HeLa tumor-bearing mouse model./nResults: On one hand, the released NO could deplete collagen by activating matrix metalloproteinases (MMPs) to break collagen fibers, thus loosening the dense ECM to enhance the cellular internalization. On the other hand, with the mitochondrial-targeted effect of TPP, the diffusible NO in tumor might rapidly interact with superoxide anion (O₂Ÿ^-) to produce highly toxic and powerful reactive nitrogen species (RNS) -- peroxynitrite (ONOO^-), which resulted in mitochondrial damage to induce cell apoptosis. With the unique properties of mini-sized gold nanorods, the formulated nanoparticles exhibited good computed tomography (CT) and multi-spectral optoacoustic tomography (MSOT) imaging effects in precisely locating and monitoring tumor. Moreover, the antitumor efficacy of GSNP-TPPs + laser group was further confirmed by ex-vivo histological analysis of tumor tissue./nConclusion: This work points out a strategy to overcome the obstacle standing in nanoparticles penetration, and opens the door of further exploitation of NO-related theranostic systems.

中文翻译：

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负载 S-亚硝基硫醇的微型 Au@silica 纳米棒在实体瘤治疗中引起胶原蛋白消耗和线粒体损伤。


在很大程度上，致密的细胞外基质（ECM）将肿瘤细胞紧密连接起来，将肿瘤武装成一个棘手的堡垒，显着降低了纳米颗粒的递送效率和癌症治疗的整体性能。因此，有必要将实体瘤的致密基质转变为疏松状态，从而实现纳米药物的深度渗透，增强癌症治疗效果。在这里，我们制造了一种无蛋白质的胶原蛋白纳米清扫剂，三苯基溴化磷（TPP）涂层和S-亚硝基硫醇负载的微型Au@silica纳米棒（Au@SiO ₂ -SNO/PEG/TPP，GSNP-TPP），以清除运输纳米粒子的屏障，提高增强渗透性和保留（EPR）效应，从而减轻扩散阻力，实现纳米粒子的进一步渗透。/n方法：通过热敏S-亚硝基硫醇对Au@silica进行修饰，载体可以释放由于表面过热而产生的一氧化氮（NO）以及在近红外（NIR）激光照射下进行光热疗法（PTT）。通过蛋白质印迹和免疫荧光染色观察胶原蛋白消耗的水平。此外，还通过 HeLa 荷瘤小鼠模型评估了 GSNP-TPP 的双重成像和抗肿瘤效率。/n 结果：一方面，释放的 NO 可以通过激活基质金属蛋白酶（MMP）破坏胶原纤维来消耗胶原蛋白，从而放松致密的ECM以增强细胞内化。 另一方面，借助TPP的线粒体靶向作用，肿瘤中的扩散NO可能会快速与超氧阴离子（O ₂ Ÿ ^- ）相互作用，产生剧毒且强力的活性氮（RNS）——过氧亚硝酸盐（ONOO ^- ） ，导致线粒体损伤，诱导细胞凋亡。凭借微型金纳米棒的独特性能，配制的纳米颗粒在精确定位和监测肿瘤方面表现出良好的计算机断层扫描（CT）和多光谱光声断层扫描（MSOT）成像效果。此外，GSNP-TPPs + 激光组的抗肿瘤功效通过肿瘤组织的离体组织学分析得到进一步证实。/n 结论：这项工作指出了克服纳米颗粒渗透障碍的策略，并为进一步研究打开了大门。 NO 相关治疗诊断系统的开发。