Dual-targeting nuclear and mitochondrial DNA damage drives immunogenic activation via PANoptosis for synergistic...

Solid tumors often evade immunotherapy due to poor drug penetration, insufficient radical accumulation, and low immunogenicity. To address this, we engineer an injectable liquid-solid phase-transition implant (Fe₃O₄/AIPH/DDP@PLGA) that mimics an "AIM2 agonist" to trigger nuclear/mitochondrial DNA dual-damage and PANoptosis for enhanced magneto-thermal dynamic immunotherapy. The gel exhibits exceptional injectability, shape adaptability, and localized retention, enabling precise intratumoral delivery while minimizing systemic toxicity. Under alternating magnetic fields (AMF), the Fe₃O₄ component generates magnetothermal effects, triggering azo bond cleavage in AIPH for controlled •C radical release and Fe²⁺-mediated Fenton reactions with tumor-overexpressed H₂O₂. In cancer therapy, cisplatin not only amplifies ROS-induced DNA damage but also, as a widely utilized chemotherapeutic agent, induces nuclear DNA (nDNA) lesions via interstrand/intrastrand crosslinking with DNA and disruption of repair mechanisms. Cytosolic dsDNA accumulation activates AIM2-PANoptosome assembly, initiating PANoptosis, engaging multiple cell death pathways (apoptosis, pyroptosis, and necroptosis), that eradicates primary tumors and primes systemic immunity through dendritic cell activation and CD8⁺ T-cell recruitment. This dual-damage strategy overcomes penetration barriers and immunogenic "cold" tumor limitations, achieving robust anti-tumor efficacy in prostate cancer models. Our work not only deciphers the mechanistic interplay of Fe₃O₄/AIPH/DDP@PLGA as a biomimetic AIM2 activator but also pioneers a transformative paradigm for solid tumor immunotherapy through controlled radical amplification and PANoptosis induction.