Abstract：
The cGAS-STING pathway and the Mevalonate Pathway are druggable targets for vaccine adjuvant discovery. Manganese (Mn) and bisphosphonates are known to exert adjuvant effects by targeting these two pathways, respectively. This study found the synergistic potential of the two pathways in enhancing immune response. Risedronate (Ris) significantly amplified the Mn adjuvant early antibody response by 166-fold and fortified its cellular immunity. However, direct combination of Mn2+ and Ris resulted in increased adjuvant toxicity (40% mouse mortality). By the combination of doping property of hydroxyapatite (HA) and its high affinity for Ris, we designed Ris-functionalized Mn-HA micro-nanoparticles as an organic-inorganic hybrid adjuvant, named MnHARis. MnHARis alleviated adjuvant toxicity (100% vs. 60% survival rate) and exhibited good long-term stability. When formulated with the varicella-zoster virus glycoprotein E (gE) antigen, MnHARis triggered a 274.3-fold increase in IgG titers and a 61.3-fold surge in neutralization titers while maintaining a better long-term humoral immunity compared to the aluminum adjuvant. Its efficacy spanned other antigens, including ovalbumin, HPV18 VLP, and SARS-CoV-2 spike protein. Notably, the cellular immunity elicited by the group of gE + MnHARis was comparable to the renowned Shingrix®. Moreover, intratumoral co-administration with an anti-trophoblast cell surface antigen 2 nanobody revealed synergistic antitumor capabilities. These findings underscore the potential of MnHARis as a potent adjuvant for augmenting vaccine immune responses and improving cancer immunotherapy outcomes.
摘要：
cGAS-STING途径和甲羟戊酸途径是疫苗佐剂发现的药物靶标。已知锰（Mn）和双膦酸盐通过靶向这两种途径发挥佐剂作用，分别。这项研究发现了两种途径在增强免疫应答中的协同潜力。利塞膦酸盐（Ris）显着将Mn佐剂的早期抗体反应放大了166倍，并增强了其细胞免疫力。然而,Mn2+和Ris的直接组合导致佐剂毒性增加(40%小鼠死亡率)。通过结合羟基磷灰石(HA)的掺杂特性及其对Ris的高亲和力,我们设计了Ris功能化的Mn-HA微纳米颗粒作为有机-无机杂化佐剂，名叫MnHARIS。MnHARis减轻佐剂毒性(100%vs.60％的存活率）并表现出良好的长期稳定性。当与水痘带状疱疹病毒糖蛋白E（gE）抗原一起配制时，MnHARis触发了IgG滴度的274.3倍增加和中和滴度的61.3倍激增，同时与铝佐剂相比保持了更好的长期体液免疫。它的功效跨越了其他抗原，包括卵清蛋白,HPV18VLP,和SARS-CoV-2刺突蛋白。值得注意的是,gE+MnHARis组引起的细胞免疫与著名的Shingrix®相当。此外，与抗滋养细胞表面抗原2纳米抗体的肿瘤内共同给药显示出协同抗肿瘤能力。这些发现强调了MnHARis作为增强疫苗免疫反应和改善癌症免疫治疗结果的有效佐剂的潜力。
