Engineered platelets-based nano-aircraft system for precise tumor chemo-immunotherapy with graded drug delivery and self-recognized tumor targeting.

Metastasis and heterogeneity pose major challenges in cancer treatment. Although chemoimmunotherapy shows promising efficacy, its therapeutic impact is limited by off-target effects and differences in the delivery sites of chemotherapeutic drugs and immunosuppressants. In this study, an engineered platelets (Pts)-based nano-aircraft, Pts@DOX/HANGs@Gal, was constructed with an internally loaded chemotherapeutic drug, doxorubicin, and externally grafted reduction-responsive hyaluronidase-cross-linked nanospheroids loaded with the immunosuppressant galunisertib for precise tumor chemo-immunotherapy. The normal physiological features of host Pts, including their excellent targeting capability for both metastatic and orthotopic tumors, are not disturbed by functional nanosystems. The interaction between Pts@DOX/HANGs@Gal and tumors gives rise to Pts activation, achieving the continuous targeted delivery of DOX to tumors, inducing the transition from cold to hot tumors, and promoting the recruitment of immune cells. Simultaneously, the external nanospheres disintegrate from Pts@DOX/HANGs@Gal, releasing galunisertib and hyaluronidase into the extracellular matrix to relieve immune tolerance and open up a high-speed channel for the tumor infiltration of immune cells and deep tumor penetration of the nanosystem. Consequently, Pts@DOX/HANGs@Gal not only effectively reinforced the antitumor immune response through self-recognized tumor-targeting chemo-immunotherapy and graded drug delivery but also reduced tumor metastasis in vivo. This study presents promising Pt-based nanovesicles for precise cancer treatment.