Nanovaccine enables complement system inhibition and high-dose AAV re-administration

Adeno-associated virus (AAV) has been extensively employed in gene therapy owing to its outstanding safety profile and low immunogenicity. AAV vector-mediated gene therapy necessitates repeated administrations to achieve prolonged therapeutic efficacy. However, clinical trials have demonstrated that subsequent to the initial administration of AAV, the host mounts an immune response against the vectors, thereby hindering the clinical feasibility of repeated AAV administration. Moreover, when the AAV dosage exceeds 1.0 × 10 13 vg/kg, there is a significant risk of excessive activation of the complement system, which can result in severe adverse reactions. Notably, research indicates that merely depleting IgG antibodies does not enable high-dose re-administration of AAV or alleviate excessive complement activation; IgM antibodies also play a pivotal role in both the immune response against AAV and complement system activation. In this study, we synthesized a series of rapamycin lipid prodrugs utilizing succinic anhydride as a chemical linker and co-assembled them with dexamethasone palmitate to produce co-assembled nanoparticles ranging from 100 to 180 nm in size. These co-assembled nanoparticles are capable of inducing regulatory T cell (Treg) generation while inhibiting T follicular helper (Tfh) cell formation, thus reducing germinal center B (GC B) cell production and consequently suppressing anti-AAV IgG and IgM antibody responses along with complement system activation. The findings suggest that these rapamycin lipid prodrug co-assembled nanoparticles facilitate high-dose re-administration of AAV while enhancing gene expression delivered by the vector.