Senescent Cell Derived Artificial Vesicle‐Based Senolytic Sonovaccine Platform with Augmented Lymph Node Delivery and Antigen Cross‐Presentation Efficacy

ABSTRACT The efficacy of senolytic vaccines aiming to clear senescent cells is limited by narrow antigen coverage and inefficient CD8 + T cell priming due to poor lymph node (LN) accumulation and inefficient antigen cross‐presentation. Here, we report SenoVac, a modular dual‐component nanovaccine platform explicitly consisting of two sequentially administered key components: an “albumin hitchhiking” DSPE‐PEG‐DBCO conjugate, and azide‐functionalized senescent cell‐derived artificial vesicles (SCAVs) that co‐encapsulate the sonosensitizer hematoporphyrin monomethyl ether (HMME) and the TLR7/8 agonist adjuvant resiquimod (R848). The first administered DSPE‐PEG‐DBCO conjugate leverages endogenous albumin transport to traffic efficiently to LNs, where it installs bioorthogonal DBCO docking sites; the subsequent administration of SenoVac's azide‐functionalized SCAVs facilitates specific and sustained accumulation in LNs via click chemistry. In the LNs, local therapeutic ultrasound irradiation activates HMME to generate reactive oxygen species (ROS), which disrupt dendritic cell endosomal membranes, promoting senescence‐associated antigens (SAAs) escape into the cytoplasm and robust cross‐presentation to CD8 + T cells. In an ApoE −/− mouse model of atherosclerosis, this integrated platform effectively cleared plaque senescent cells, attenuated disease progression, and showed a favorable safety profile. Our work establishes a translatable strategy that combines active LN targeting with stimulus‐responsive cross‐presentation enhancement for senolytic immunotherapy.