Extracellular vesicles delivered rapamycin to improve the tumor microenvironment and enhance hepatocellular carcinoma immunotherapy.

Hepatocellular carcinoma (HCC) is one of the most common and lethal malignancies worldwide with limited therapeutic options due to its tumor immunosuppressive microenvironment (TIME). Herein, we engineered extracellular vehicles (EVs) derived from hepatocellular carcinoma cells to encapsulate rapamycin-loaded nanoparticles (Rapa-EVs) for precision HCC therapy. The experimental results demonstrated that the Rapa-EVs improved water solubility and stability. Rapa-EVs showed a high cellular uptake rate and could effectively target tumor tissues, promote dendritic cell (DC) maturation, and thereby activated CD8 + T cells. They directly inhibited H22 cell proliferation, promoted macrophage M1 polarization. Rapa-EVs also normalized aberrant tumor vasculature to improve drug perfusion and immune cell infiltration, inhibited tumor metastasis. This design synergistically harnesses the natural tumor-targeting properties of EVs to achieve rapamycin-selective delivery, concurrently leveraging their intrinsic immunogenicity to prime antitumor immunity while coordinating rapamycin-mediated TIME remodeling. Through comprehensive in vitro and in vivo evaluations, our study establishes a paradigm for HCC therapy that integrates biomimetic drug delivery with microenvironmental modulation, offering a transformative approach to overcome treatment resistance and improve patient outcomes.