Platelet hitchhiking vascular-disrupting agents for self-amplified tumor-targeting therapy

The vascular-disrupting agent DMXAA (5,6-dimethylxanthone-4-acetic acid) exhibits potent anticancer activity by targeting tumor vasculature and activating immune responses via the cGAS-STING pathway. However, its clinical application is hindered by nonspecific targeting and significant cardiovascular toxicity. This study introduces a novel self-amplified tumor-targeting delivery system(P@NPPD)comprising azide-functionalized poly(ethylene glycol)- b -poly-[( N -2-hydroxyethyl)-aspartamide]-DMXAA (N 3 -PEG- b -PHEA-DMXAA, NPPD) conjugated to DBCO modified platelets. Among them, NPPD was synthesized by conjugating DMXAA to N 3 -PEG- b -poly-[( N -2-hydroxyethyl)-aspartamide] through esterification. This system enhances tumor-specific drug delivery while minimizing systemic toxicity. Leveraging the natural tumor-homing properties of platelets and the coagulation cascade, P@NPPD selectively targets exposed collagen at tumor sites, initiating a self-amplifying release of DMXAA. This approach achieved a 2.61-fold improvement in targeting efficiency and an 89.1% tumor suppression rate. In addition to improving drug accumulation at tumor sites, P@NPPD significantly activated local immune responses, enhancing therapeutic efficacy and safety. These findings underscore the potential of P@NPPD as a promising platform for cancer therapy. Graphical abstract