Pharmacologically programmed tolerogenic dendritic cell membrane-coated nanoparticles for CCR7-dependent lymphoid organ targeting in transplantation

Secondary lymphoid organs (SLOs) are critical sites for alloimmune activation and attractive targets for transplantation immunotherapy. However, current cell membrane-based targeting strategies face a fundamental trade-off between low immunogenicity and efficient SLO homing, limiting their therapeutic potential. To resolve this functional trade-off, we developed a biomimetic delivery system (PD-DmRK) by coating self-assembled RapaLink-1 (RK) nanoparticles with cell membranes derived from PP242 and docosahexaenoic acid (DHA)-induced tolerogenic dendritic cells (TolDCs). Compared with conventional tolerogenic induction strategies, PP242/DHA preserved low immunogenicity and markedly increased CCR7 expression, thereby improving SLO targeting. Mechanistically, PP242 and DHA cooperatively activated the transcription factor USF2, which directly bound to the Ccr7 promoter and transcriptionally upregulated Ccr7 expression. Consequently, PD-DmRK exhibited enhanced accumulation in SLOs, reduced hepatic and renal sequestration, and significantly prolonged skin and cardiac allograft survival. High-dimensional spectral flow cytometry and single-cell transcriptomic analyses further indicated that PD-DmRK treatment was associated with enrichment of Ccr9-expressing plasmacytoid dendritic cells and regulatory T cells, accompanied by reduced cytotoxic T-cell responses. Overall, PD-DmRK provides a TolDC membrane platform in which the USF2-CCR7 axis links immunoregulatory activity with CCR7-dependent SLO targeting, supporting its potential for targeted immunotherapy in transplantation.