Hijacking dead tumor cells for lung-targeted and gene-augmented cuproptosis therapy.

Cuproptosis holds transformative potential for treating pulmonary malignancies, yet its efficacy is hindered by the poor lung-targeting of inducers and metabolic resistance mediated by the copper efflux transporter ATP7A. Inspired by pulmonary capillary filtration, we developed DACu, a biomimetic system based on inactivated tumor cells that integrates targeted gene therapy with metabolic and immune modulation. DACu encapsulates an adeno-associated virus (AAV)-mediated, tumor-specific ATP7A-knockout cassette and is surface-anchored with albumin nanoparticles loading copper diethyldithiocarbamate (CuET, a copper complex of FDA-approved disulfiram). While this cell-nanoparticle hybrid architecture resolves the challenges of loading poorly soluble small-molecule drugs, DACu achieves efficient enrichment in pulmonary lesions via its inherent capillary entrapment and homotypic adhesion mechanisms, yielding a ∼120-fold increase in viral enrichment. It further provides an immune shield for AAV, mitigating neutralizing antibody interference. Within the tumor microenvironment, DACu disintegrates to trigger "Trojan horse" AAV release and CuET nanoparticles dissociation, enabling precise ATP7A knockout to establish an efflux blockade-influx amplification network that forces intracellular copper stress to lethal thresholds. Furthermore, cuproptosis-induced stress synergizes with DACu-derived tumor antigens as an in situ vaccine, activating systemic T cell immunity. DACu effectively eradicates primary lung tumors and melanoma metastases, providing a paradigm for overcoming multidimensional resistance.