Genetically Programmable Biohybrid Nanoplatform Enables Cuproptosis‐Immunotherapy via Spatiotemporal Control of Macrophage Polarization and Copper Flux

Abstract Tumor‐associated macrophages (TAMs), particularly the M2 phenotype, play pivotal roles in tumor metastasis and immune evasion. However, current phenotypic modulation strategies are constrained by inherent limitations, including indirect regulation dependent on tumor signals and imprecise polarization control. Moreover, the cooperative copper transport mechanism between TAMs (as copper donors) and tumor cells is still unknown in antitumor therapy. Here, a clustered regularly interspaced short palindromic repeats‐associated protein 9 (CRISPR‐Cas9)‐engineered biohybrid material (B cp DCHD) is developed to synchronize cuproptosis induction and immunotherapy by precisely reprogramming TAMs phenotype and copper trafficking. Upon specific attachment to M2‐TAMs, B cp DCHD undergoes charge reversal to accelerate endocytosis and delivers Cas9‐sgRNA complexes for editing the immunosuppressive hub gene Pik3cg , effectively driving M2‐to‐M1 repolarization and destroying immunosuppressive niche. Concurrently, this phenotypic switch upregulates copper transport network proteins and activates the CD44/HA‐Cu uptake axis, amplifying local copper accumulation in tumor cells. The resultant copper overload triggers cuproptosis while simultaneously activating antitumor immunity through immunogenic cell death. It is demonstrated that B cp DCHD overcomes the spatial‐temporal limitations of conventional approaches by directly editing TAMs and hijacking their copper metabolic crosstalk with tumor cells, opening a new dimension in cancer treatment.