Apoptotic Cell-Mimicking Nanocarriers Enhance Splenic Red Pulp Delivery through Lipid Pool Modulation

Spleen-targeted nanovaccines hold promise for enhancing immune responses and protective effect, yet their effectiveness is hindered by challenges such as inevitable liver retention, limited speed of immune activation, and poor biocompatibility. Natural lipids typically possess excellent biocompatibility, allowing for favorable interactions with cells and tissues in the body, thereby reducing immune responses and toxicity. In this study, we proposed a selective spleen-targeting strategy for custom designing the nanocarriers utilizing the biomimetic concept of apoptotic cell membranes and natural lipid pool modulation. These optimized nanocarriers can effectively target the spleen's red pulp, contributing to the development of spleen-targeted nanovaccines. As a proof of concept, we fabricated a spleen-targeted nanovaccine against the influenza virus. 2 h after systemic injection, the spleen-targeted nanovaccines were able to be specifically taken up by 77.9% of macrophages and 28.6% of dendritic cells in the splenic red pulp region, effectively inducing B and T cell responses in vivo within 7 days. Moreover, spleen-targeted nanovaccines exhibited high antigen encapsulation efficiency, good storage stability, and low leakage, which enhanced their potential for successful commercialization. This strategy is designed to address the immune efficacy and biosafety of spleen-targeted vaccine formulations.