Peptide-MHC-targeted engineered virus-like particles enable selective priming and gene editing of tumor-specific T...

Tumor-infiltrating lymphocyte (TIL) therapies harness tumor-specific T cells endogenous to a patient's repertoire but their efficacy is limited by challenges such as low frequencies of tumor-specific clonotypes and dysfunctional T cell phenotypes. These challenges necessitate technologies to engineer and reprogram endogenous tumor-specific TILs ex vivo. Here, we present a strategy using engineered virus-like particles (eVLPs) pseudotyped with peptide-major histocompatibility complexes (pMHCs) as a programmable, single-effector platform for selective and coordinated priming, expansion, and genome editing of rare antigen-specific CD8⁺ T cells among their endogenous polyclonal repertoires. We demonstrate that pMHC-pseudotyped eVLPs (pMHC-eVLPs) deliver T cell function-enhancing base editors to arm polyclonal lymphocytes with enhanced anti-tumor cytotoxicity by selectively expanding and engineering the tumor-specific T cell compartment. Our work establishes pMHC-eVLPs as a platform for enhancing TIL therapy with precision gene edits without the risks of bystander T cell engineering associated with polyclonal TIL engineering approaches.