Suicide gene therapy holds great promise for cancer treatment, exhibiting potent efficacy across diverse tumor types. However, its clinical application remains hampered by insufficient tumor selectivity and systemic toxicity. Here, we developed tumor-specific suicide gene nanomedicines that selectively eliminate cancer cells while sparing healthy tissues. These nanomedicines comprise lipid-assisted polymeric nanoparticles encapsulating plasmids driven by tumor-specific promoters, enabling selective expression of a mutant herpes simplex virus thymidine kinase (SR39TK) in tumor cells. The expressed SR39TK converts the prodrug ganciclovir (GCV) into its cytotoxic triphosphate form (GCV-PPP), inducing tumor-specific apoptosis. Notably, the tyrosinase promoter-driven NP_Tyr-SR39TK enables melanoma-specific expression and strong antitumor efficacy, whereas replacing the tyrosinase promoter with a survivin promoter yields NP_Sur-SR39TK, which extends this precision cytotoxicity to other tumor types while maintaining safety in normal tissues. Overall, this study introduces a versatile and tumor-selective gene therapy strategy, offering a promising avenue for advancing suicide gene therapy.

B cells exert multiple effector functions, and dysfunctions of B cells often lead to initiation and progression of diseases, including autoimmune and inflammatory diseases. Therefore, B cell intervention may be an effective strategy to treat diseases involving B cells. The clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 gene editing system has been widely used for DNA deletion, insertion, and replacement. Nanocarriers have been developed as relatively mature systems and may be applied to deliver the CRISPR-Cas9 system to B cells in vivo. In this study, we created a library of nanoparticles (NPs) with different polyethylene glycol densities and zeta potentials and screened an optimal NP for in vivo B cell targeting. The selected NP could deliver the CRISPR-Cas9 system to B cells and induce Cas9 expression inside the cell environment. Injection of the NP encapsulated with Cas9/gB220 (NP_Cas9/gB220) into mice could disrupt B220 expression in B cells, suggestive of its applications to intervene the expression of the target molecule in B cells. Moreover, the treatment with NP_Cas9/gBAFFR could decrease the number of B cells and exert therapeutic effect in rheumatoid arthritis, as B-cell activating factor receptor (BAFFR) is vital for the survival and functions of B cells. In conclusion, we developed a carrier for the delivery of the CRISPR-Cas9 gene editing system for B cell intervention that could be used for the treatment of diseases related to B cell dysfunctions.