The anticancer performance of nanomedicine is largely impeded by insufficient intratumoral penetration. Herein, tumor microenvironment (TME)-amendatory and self-adaptive nanoclusters (NCs) capable of cancer-associated fibroblasts (CAFs) depletion and size/charge conversion were engineered to mediate light-assisted, hierarchical intratumoral penetration. Particularly, large-sized NCs (~50 nm) were prepared via self-assembly of FAP-α-targeting peptide-modified, ¹O₂-sensitive polymers, which were further used to envelope small-sized dendrimer (~5 nm) conjugated with Ce6 and loaded with DOX (DC/D). After systemic administration, the NCs efficiently targeted CAFs and generated lethal levels of ¹O₂ upon light irradiation, which depleted CAFs and concomitantly dissociated the NCs to liberate small-sized, positively charged DC/D. Such stroma attenuation and NCs transformation collectively facilitated the delivery of DC/D into deeper regions of CAF-rich tumors, where DOX and ¹O₂ provoked synergistic anti-cancer efficacies. This study provides an effective approach to facilitate the tumor penetration of nanomedicine by concurrently and spatiotemporally reconfiguring the nano-properties and remodeling the TME.

纳米药物的抗癌性能在很大程度上受到肿瘤内穿透不足的阻碍。本文中，设计了能够与癌症相关的成纤维细胞（CAF）耗竭和大小/电荷转换的肿瘤微环境（TME）修正和自适应纳米簇（NCs），以介导光辅助的分级肿瘤内穿透。特别是，通过FAP-α靶向肽修饰的¹ O ₂敏感聚合物的自组装，制备了大尺寸的NC（〜50 nm），该聚合物进一步用于包裹结合了小分子的树枝状聚合物（〜5 nm）。 Ce6并装有DOX（DC / D）。全身给药后，NC有效靶向CAF，并产生¹ O _2的致死水平。在光照射下，这会耗尽CAF，并随之使NC分解，从而释放出小型的带正电荷的DC / D。这样的基质衰减和NCs转化共同促进了DC / D传递到富含CAF的肿瘤的更深区域，其中DOX和¹ O _2具有协同抗癌作用。这项研究提供了一种有效的方法，可通过同时和时空重新配置纳米特性并重塑TME来促进纳米药物在肿瘤中的渗透。