Safe and Localized Lentiviral Gene Delivery via Injectable Mesoporous Scaffolds for Potent Antitumor Immunity

ABSTRACT Lentiviral vectors offer potent and sustained gene expression, but their in vivo use remains limited by safety concerns, particularly the risks of systemic dissemination and insertional mutagenesis. To address these limitations, we present a spatially confined lentiviral gene delivery method that enables safe and efficient in vivo targeted transduction of dendritic cells (DCs) via a modular injectable scaffold. By attaching lentiviral vectors encoding a tumor antigen on the surface of mesoporous silica scaffold preloaded with granulocyte‐macrophage colony‐stimulating factor, we create a self‐assembling scaffold that recruits DCs and promotes their localized transduction. This platform minimizes systemic vector dissemination and restricts genome integration to recruited immune cells, enabling prolonged antigen expression and efficient MHC‐I‐mediated antigen presentation. In melanoma models, this method elicits robust antigen‐specific CD8 + T‐cell responses, enhances effector memory generation, and improves antitumor immunity. Combination with immune checkpoint blockade further potentiates therapeutic outcomes. This strategy establishes a versatile and safe in vivo lentiviral delivery system with potential applications across cancer, infectious, and autoimmune diseases.