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bioRxiv · 10.64898/2026.04.08.717283

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

Kim, G.·Wang, S.·Zhu, R.·Webber, M. J.·Lu, X.·Wang, Y.
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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. HIGHLIGHTSO_LIDC-sEVs preserve antigen presentation, T-cell activation, and lymph node targeting C_LIO_LIChirality-assisted loading with pH-responsive functionalization enables efficient cytosolic delivery while maintaining membrane bioactivity C_LIO_LIEngineered DC-sEVs combine in situ T-cell priming and PD-1 silencing to enhance effector function C_LIO_LIIn situ T-cell reprogramming drives potent antitumor efficacy and favorable tumor microenvironment remodeling C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/717283v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@e3b05org.highwire.dtl.DTLVardef@44febcorg.highwire.dtl.DTLVardef@1b00479org.highwire.dtl.DTLVardef@f5db2a_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Kim, G., Wang, S., Zhu, R., Webber, M. J., Lu, X., Wang, Y.. 2026-04-11. Dual-Engineered Dendritic Cell Derived Small Extracellular Vesicles Couple T Cell Priming with Checkpoint Reprogramming for Synergistic Immunotherapy. https://doi.org/10.64898/2026.04.08.717283

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