Dual-Engineered Dendritic Cell–Derived Small Extracellular Vesicles Couple T-Cell Priming with Checkpoint Reprogramming for Synergistic Immunotherapy

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Abstract
Immunotherapy has transformed cancer treatment, yet cell-based therapies remain complex and costly, and immune checkpoint blockade (ICB) agents often suffer from limited stability and poor T-cell selectivity. Here, we develop an engineered dendritic cell–derived small extracellular vesicle (DC-sEV) nanoplatform for combinatorial immunotherapy via in situ T-cell activation and checkpoint reprogramming. DC-sEVs preserve intrinsic dendritic-cell immunobiology, enabling antigen presentation and potent T-cell activation. We further integrate high-efficiency cargo loading and membrane functionalization to selectively deliver ICB payloads to T cells, achieving dual reprogramming that sustains effector function and amplifies antitumor immunity. This approach reduced cancer cell viability to 44.05% in vitro and produced 82.12% tumor growth inhibition in vivo , establishing DC-sEVs as a targeted, scalable cell-free immunotherapy platform. HIGHLIGHTS: DC-sEVs preserve antigen presentation, T-cell activation, and lymph node targeting Chirality-assisted loading with pH-responsive functionalization enables efficient cytosolic delivery while maintaining membrane bioactivity Engineered DC-sEVs combine in situ T-cell priming and PD-1 silencing to enhance effector function In situ T-cell reprogramming drives potent antitumor efficacy and favorable tumor microenvironment remodeling GRAPHICAL

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