Bioengineered Anti-PD-L1 Functionalized Nanoplatform for Targeted Delivery and Tumor Immune Reprogramming Against Colorectal Cancer.

Colorectal cancer (CRC) remains a major clinical challenge owing to its immunosuppressive tumor microenvironment and limited targeting therapeutic efficiency. Developing innovative strategies that integrate immune activation with enhanced tumor-targeting ability is urgently needed. Herein, we reported a bioengineered exosome drug delivery nanoplatform (Apatinib-Exo(aPD-L1)), in which HEK293T-derived exosomes were surface functionalized with anti-PD-L1 antibody (aPD-L1) and encapsulated the tyrosine kinase inhibitor Apatinib, aiming to enhance the tumor-targeted immunotherapy against CRC. Apatinib-Exo(aPD-L1) exhibited efficient tumor-targeting capability and prolonged systemic circulation, attributed to aPD-L1 modification, resulting in markedly enhanced antitumor efficacy without evident body toxicity. Mechanistically, Apatinib was efficiently delivered and internalized by tumor cells, where it triggered immunogenic cell death (ICD) and promoted dendritic cell maturation. This immune activation cascade facilitated the infiltration and activation of cytotoxic T cells within the tumor microenvironment. Furthermore, Apatinib-Exo(aPD-L1) reduced the population and suppressive function of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), thereby effectively reversing immune suppression and amplifying the antitumor immune response. Collectively, our findings demonstrated that Apatinib-Exo(aPD-L1) is a safe and effective exosome-based therapeutic platform, offering a promising strategy to convert immunologically "cold" tumors into "hot" ones and improve clinical outcomes in CRC.