Insufficient drug release and poor drug penetration compromise the efficacy of chemotherapy and hinder clinical translations in nanoparticle-based drug delivery systems. Inspired by the excretion process of exosomes, herein, silk fibroin-based doxorubicin preloaded calcium carbonates (CCs-SF/DOX) that integrate tumor-derived extracellular vesicle (EV) generation attributes are constructed for triple therapies of “local chemotherapy–therapeutic EVs–synergistic immunotherapy” (CT–EVs–IT). Assisted by low-intensity focused ultrasound, increased intracellular influx of CCs-SF/DOX can be achieved through acoustic pertubation-facilitated delivery or endocytic uptake. The acidic endosome or lysosome accelerates the release of DOX in the cancer cells for efficient cytotoxicity. Residual CCs-SF/DOX or uploaded DOX from dead/dying cells are encapsulated in vesicles and fuse with the plasma membrane of cells, triggering excretion of vesicles to extracellular space and responding to the acidic environment in the ECM, repeating the process infecting neighboring cancer cells, and exerting deep drug penetration based EV therapy. Meanwhile, CCs-SF/DOX scavenging of H⁺ promotes M1-like macrophage polarization, reversing immunosuppressive TME, and locally released chemotherapeutics potentiate antitumor immune response; both facilitate PD1/PD-L1 checkpoint blockade combined immunotherapy. Taken together, therapies of CT–EVs–IT assisted by LIFU contribute to achieve amplified antitumor benefits.

中文翻译：

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低强度聚焦超声辅助纳米复合材料用于晚期三重癌症治疗：局部化疗，治疗性细胞外囊泡和联合免疫疗法

药物释放不足和药物渗透不良会损害化学疗法的功效，并阻碍基于纳米颗粒的药物递送系统中的临床翻译。受外泌体排泄过程的启发，此处整合了肿瘤衍生的细胞外囊泡（EV）生成属性的基于丝素蛋白的阿霉素预载碳酸钙（CCs-SF / DOX）被构建用于“局部化学疗法-治疗性EV-协同免疫疗法”（CT–EVs–IT）。在低强度聚焦超声的辅助下，可以通过声波插管促进的递送或内吞摄取来增加CCs-SF / DOX的细胞内流入。酸性内体或溶酶体可促进癌细胞中DOX的释放，从而实现有效的细胞毒性。来自死/垂死细胞的残留CCs-SF / DOX或上载的DOX被封装在囊泡中，并与细胞的质膜融合，触发囊泡排泄到细胞外空间，并对ECM中的酸性环境作出反应，重复此过程以感染邻近的癌症细胞，并基于EV进行深层药物渗透。同时，清除H的CCs-SF / DOX⁺促进M1样巨噬细胞极化，逆转免疫抑制TME，局部释放的化疗药物增强抗肿瘤免疫反应；两者都有助于PD1 / PD-L1检查点阻断联合免疫疗法。综上所述，在LIFU的帮助下，CT–EVs–IT的治疗有助于获得更大的抗肿瘤益处。