STING activation disrupts tumor vasculature to overcome the EPR limitation and increase drug deposition.

The low success rate of cancer nanomedicines has raised debate on the role of the enhanced permeability and retention (EPR) effect on tumor deposition of nanotherapeutics. Here, we report a bifunctional nanoscale coordination polymer (NCP), oxaliplatin (OX)/2',3'-cyclic guanosine monophosphate-adenosine monophosphate (GA), to overcome the EPR limitation through stimulator of interferon genes (STING) activation and enhance chemotherapeutic and STING agonist delivery for tumor eradication. OX/GA encapsulates GA and OX in the NCP to protect GA from enzymatic degradation and improve GA and OX pharmacokinetics. STING activation by OX/GA disrupts tumor vasculatures and increases intratumoral deposition of OX by 4.9-fold over monotherapy OX-NCP. OX/GA demonstrates exceptional antitumor effects with >95% tumor growth inhibition and high cure rates in subcutaneous, orthotopic, spontaneous, and metastatic tumor models. OX/GA induces immunogenic cell death of tumor cells and STING activation of innate immune cells to enhance antigen presentation. NCPs provide an excellent nanoplatform to overcome the EPR limitation for effective cancer therapy.