Precisely Amplifying Intracellular Oxidative Storm by Metal-Organic Coordination Polymers to Augment Anticancer...

Oxidative stress accompanying the reactive oxygen species (ROS) burst governs immunocyte infiltration, activation, and differentiation in tumor microenvironments and thus can elicit robust antitumor immunity. Here, we identify a photoactive metal-organic coordination polymer (MOCP), composed of an organometallic core formed by cytotoxic mitoxantrone (MTX) acylates and photosensitive Ru(BIQ)-HDBB [BIQ = 2,2'-biquinoline, HDBB = 4,4'-di(4-benzoato)-2,2'-bipyridine] linked by Fe(II) ions via coordinate covalent bonds and an amphipathic shell encapsulating cholesterol-modified siRNA against GPX4 (siGPX4) via hydrophobic force, to precisely amplify intracellular oxidative storm. MOCPs simultaneously encapsulated MTX, Ru, and siGPX4 with efficiencies >98% and loaded Fe with efficiencies of ∼0.49%. With longer blood circulation and higher tumor accumulation, MOCPs with a 670 nm LED irradiation generate abundant ROS to induce biomembrane dysfunction and subsequently contribute to ferroptotic and immunogenic cell death, which drive tumor-associated antigen-specific immunity. MTX analogs contributed to Type I immunogenic cell death (ICD), while oxidative storm served as a damager for endo/lysosomal escape, an initiator for ferroptosis, and an inducer for type II ICD. Moreover, the blockade of CD73 that reduces extoATP catabolism unleashes immunosuppression, finally enhancing antitumor immune stimulation of MOCPs to promote orthotopic mammary cancer regression and prevent postoperative advanced cancer from recurrence and metastasis. MOCPs by exposing sufficient antigenicity thus provide a platform to synergize immune checkpoint inhibitors for the treatment of immunologically cold tumors.