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 @二氧化硅纳米棒在实体瘤治疗中引起胶原蛋白耗竭和线粒体损伤。

在很大程度上，致密的细胞外基质（ECM）紧密地连接肿瘤细胞，将肿瘤武装到顽固的堡垒中，大大降低了纳米颗粒在癌症治疗中的递送功效和整体性能。因此，有必要将实体瘤的致密基质转变为松散状态，以实现纳米药物的深层渗透并增强癌症治疗效果。在这里，我们制造了无蛋白的胶原纳米扫除剂，三苯基溴化bro（TPP）涂层和S-亚硝基硫醇负载的微型Au @二氧化硅纳米棒（Au @ SiO ₂-SnO / PEG / TPP，GSNP-TPP），以清除纳米颗粒的运输障碍以及增强ELEVATE的渗透性和保留（EPR）效果，从而减轻扩散阻力，实现nanoparticles./n的进一步渗透方法：通过修改在具有热敏性S-亚硝基硫醇的Au @二氧化硅中，由于表面过热，载体可以释放一氧化氮（NO），并且可以在近红外（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到胶原蛋白的消耗水平。此外，双成像和GSNP-TPP的抗肿瘤效率用的HeLa细胞荷瘤小鼠model./n评价结果：一方面，释放出的NO可以通过激活基质金属蛋白酶（MMP）破坏胶原纤维，从而消耗胶原蛋白，从而疏松致密的ECM以增强细胞内在化。在另一方面，与TPP，可扩散NO在肿瘤的靶向线粒体的效果可能迅速相互作用与超氧阴离子（O ₂ Ÿ ^- ），以产生高毒性的和强大的活性氮（RNS） -过氧亚硝酸盐（ONOO ^-），导致线粒体损伤，诱导细胞凋亡。具有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）和多光谱光声层析成像（MSOT）成像效果。此外，通过肿瘤组织的离体组织学分析进一步证实了GSNP-TPPs +激光组的抗肿瘤功效。/n结论：这项工作指出了克服纳米颗粒穿透障碍的策略，并为进一步打开大门开发与NO相关的诊断系统。