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

Abstract

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.