Novel co-delivery nanomedicine for photodynamic enlarged immunotherapy by cascade immune activation and efficient Immunosuppression reversion.

Photodynamic therapy (PDT) combined with immunotherapy has become a promising antitumor strategy. However, precise regulation of the activation of antitumor immunity and effective reversion of immunosuppressive tumor microenvironment (TME) remains challenging. In this paper, a novel co-delivery nanomedicine is developed to solve these issues for photodynamic amplified immunotherapy. Specifically, the glycolysis inhibitor (Lon) is coupled with PD1/PDL1 blocker (BMS-1) by thioketal linkage to form smartly responsive prodrug LTB, which could further encapsulate photosensitizer chlorine e6 (Ce6) to construct a co-delivery nanoplatform (LTB-6 NPs) by self-assembly. Of note, LTB-6 NPs possess favorable stability, uniform morphology and improved cellular uptake. More importantly, LTB-6 NPs are capable of inhibiting glycolysis and blocking PD1/PDL1, which could greatly improve the immunosuppressive TME to promote immune activation. LTB-6 NPs-mediated PDT not only inhibits tumor proliferation but also induces ICD response to activate immunological cascade. In vivo experiments indicate that intravenously injected LTB-6 NPs remarkably suppresses the tumor growth while leads to a minimized side effect. This research provides a multi-synergized strategy for developing effective photodynamic nanoplatforms in tumor treatment.