The complex blood environment, heterogenic enhanced permeability and retention (EPR) effect, and dense matrix comprise the primary “leakage obstacles” impeding specific accumulation and penetration of nanodrugs against solid tumors, thus forming a key bottleneck for their clinical application. Herein, we present a biomineralization-inspired dasatinib (DAS) nanodrug (CIPHD/DAS) that sequentially permeates all of the abovementioned hindrances for efficient treatment of solid tumors. CIPHD/DAS exhibited a robust hybrid structure constructed from an iRGD-modified hyaluronic acid-deoxycholic acid organic core and a calcium phosphate mineral shell. In vitro and in vivo data demonstrated the mechanism of sequential tumoral infiltration was based on mineral-stiffened blood circulation with decreased premature drug leakage, iRGD-endowed tumor-specific transendothelial transport for “first-order promotion of accumulation” and DAS-mediated restoration of fibrotic stromal homeostasis for “second-order promotion of penetration”. Resultantly, CIPHD/DAS showed remarkable distal drug availability in desmoplastic 4T1/CAFs orthotropic mouse models and significantly suppressed tumor growth and metastasis. This optimized strategy with sequential permeabilization of the capital “leakage obstacles” validates a promising paradigm to conquer the “impaired delivery and penetration” associated bottleneck of nanodrugs in the clinical treatment of solid tumors.

复杂的血液环境，异质性增强的通透性和保留（EPR）效果以及致密的基质构成了主要的“泄漏障碍”，阻碍了纳米药物对实体瘤的特异性积累和渗透，从而形成了其临床应用的关键瓶颈。在本文中，我们介绍了一种受生物矿化作用启发的达沙替尼（DAS）纳米药物（CIPHD / DAS），该药物顺序渗透所有上述障碍，以有效治疗实体瘤。CIPHD / DAS展示了由iRGD修饰的透明质酸-脱氧胆酸有机核和磷酸钙矿物壳构成的稳健的杂化结构。体外和体内数据表明，顺序性肿瘤浸润的机制是基于矿物质强化的血液循环，减少了过早的药物泄漏，iRGD赋予了肿瘤特异性的跨内皮运输以“促进一级蓄积”，DAS介导的纤维化基质稳态恢复为“二级渗透”。结果，CIPHD / DAS在增生的4T1 / CAFs正交各向异性小鼠模型中显示出显着的远端药物可利用性，并显着抑制了肿瘤的生长和转移。这种优化的策略具有顺序性的资本“泄漏障碍”通透性，验证了一种有前途的范例，可以克服实体药物临床治疗中与“受损的传递和渗透”相关的纳米药物瓶颈。