A versatile VLP-mediated CRISPR-RNP platform for precise genome editing and durable epigenome silencing in cancer

Clustered regularly interspaced short palindromic repeats (CRISPR)-based genome and epigenome editing hold great promise for precision therapy, yet their clinical translation is limited by delivery challenges. Here, we present a transient, DNA-free virus-like particle (VLP) platform for the delivery of CRISPR ribonucleoprotein (RNP) across diverse cancer applications. VLP-mediated genome editing achieved high editing efficiency and broad applicability across multiple cancer types. Notably, VLP-mediated mutation-selective targeting of oncogenic alleles induced potent on-target activity and high-fidelity mutation-selective effects in cancer cells, with minimal effects on normal cells. Beyond genome editing, VLP delivery of the epigenome editor CRISPRoff effectively suppressed cancer cell growth and induced stable gene silencing maintained for over 120 days. Moreover, it provided a strategy to overcome knockout escape, a key limitation of conventional genome editing. In comparison with DNA vector-based delivery systems, VLPs enabled transient expression while achieving lower off-target activity and higher efficiency. Furthermore, the VLP platform exhibited a favorable in vivo safety profile, characterized by transient exposure and no hepatotoxicity. In a mouse xenograft model, the platform successfully suppressed tumor growth via precision targeting. Collectively, these findings establish VLP-mediated CRISPR delivery as a versatile and safe integrated delivery platform, providing a comprehensive modality for both genome and epigenome editing in precision therapeutics.