Risedronate-Functionalized Manganese-Calcium Phosphate Nanoparticles: A Potent Adjuvant for Subunit Vaccines and Cancer Immunotherapy

Calcium phosphate (CaP) adjuvants have been employed to enhance immunity against diphtheria and tetanus antigens, as well as allergen desensitization. Despite CaP's favorable tolerability, certain drawbacks compromise its effectiveness, rendering it a less-than-optimal alternative to alum adjuvants. Addressing these limitations, we delved into a comprehensive study of risedronate-functionalized manganese-calcium phosphate nanoparticles (Mn/CaRis) - an innovative formulation derived from CaP. Our research offers compelling evidence that Mn/CaRis outperforms traditional aluminum adjuvants in enhancing antigen delivery efficiency, amplifying antibody responses, and bolstering T cell immunity. When combined with the varicella-zoster virus glycoprotein E (gE) antigen, Mn/CaRis triggered a 274.3-fold increase in IgG titers and a 61.3-fold surge in neutralization titers compared to those generated by the aluminum adjuvant. We noticed comparable enhancements in humoral immunity when Mn/CaRis served as an adjuvant for OVA, HPV18, and SARS-CoV-2 vaccines, alongside superior sustenance of long-term humoral immunity. Notably, the gE+Mn/CaRis combination mirrored the high cell-mediated immunity elicited by Shingrix®. Moreover, Mn/CaRis demonstrated a synergistic anti-cancer effect when co-administered intratumorally with anti-Trophoblast cell surface antigen 2 nano-antibody immunotherapy, exceeding the effect of single-agent use. These findings underscore the potential of Mn/CaRis as a potent adjuvant for augmenting vaccine immune responses and improving cancer immunotherapy outcomes.