Metal‐Phenolic Nanomaterial with Organelle‐Level Precision Primes Antitumor Immunity via mtDNA‐dependent cGAS‐STING Activation

Abstract New generation of nanomaterials with organelle‐level precision provide significant promise for targeted attacks on mitochondria, exhibiting remarkable therapeutic potency. Here, we report a novel amphiphilic phenolic polymer (PF) for the mitochondria‐targeted photodynamic therapy (PDT), which can trigger excessive mitochondrial DNA (mtDNA) damage by the synergistic action of oxidative stress and furan‐mediated DNA cross‐linking. Moreover, the phenolic units on PF enable further self‐assembly with Mn 2+ via metal‐phenolic coordination to form metal‐phenolic nanomaterial (PFM). We focus on the synergistic activation of the cGAS‐STING pathway by Mn 2+ and tumor‐derived mtDNA in tumor‐associated macrophages (TAMs), and subsequently repolarizing M2‐like TAMs to M1 phenotype. We highlight that PFM facilitates the cGAS‐STING‐dependent immunity at the organelle level for potent antitumor efficacy.