Neutrophil-inspired CRISPR/dCas9 nanomedicine to program self-destructing and bystander killing of tumor cell for selective cancer therapy.

Achieving high efficiency, selectivity, and durability remains a major challenge in the development of innovative cancer treatments, as current clinical therapies often fall short. Inspired by neutrophil-mediated tumor clearance, we engineered a nanocarrier-mediated CRISPR/dCas9 system to activate endogenous expression of neutrophil elastase (ELANE) for precise cancer therapy. Although ELANE was upregulated in both normal and tumor cells, selective killing occurred only in tumor cells through a histone H1.0-dependent self-destructing mechanism. Additionally, secreted ELANE further efficiently eliminated neighboring tumor cells via bystander killing. ELANE-mediated tumor cell death also induced immunogenic responses, potently enhancing antitumor immunity and synergizing with anti-PD-L1 therapy to inhibit tumor metastasis. This study presents a novel CRISPRa-based therapeutic strategy that mimic neutrophil function to achieve potent, selective, and durable tumor eradication through combined mechanisms of self-destruction, bystander killing and immune activation.