A low-intensity focused ultrasound-assisted nanocomposite for advanced triple cancer therapy: local chemotherapy, therapeutic extracellular vesicles and combined immunotherapy

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.