Risedronate-functionalized manganese-hydroxyapatite amorphous particles: A potent adjuvant for subunit vaccines and cancer immunotherapy
作者全名：Zhang, Xiuli; Wei, Mingjing; Zhang, Zhigang; Zeng, Yarong; Zou, Feihong; Zhang, Sibo; Wang, Zhiping; Chen, Fentian; Xiong, Hualong; Li, Yufang; Zhou, Lizhi; Li, Tingting; Zheng, Qingbing; Yu, Hai; Zhang, Jun; Gu, Ying; Zhao, Qinjian; Li, Shaowei; Xia, Ningshao
作者地址：[Zhang, Xiuli; Wei, Mingjing; Zhang, Zhigang; Zeng, Yarong; Zou, Feihong; Zhang, Sibo; Wang, Zhiping; Chen, Fentian; Xiong, Hualong; Li, Yufang; Zhou, Lizhi; Li, Tingting; Zheng, Qingbing; Yu, Hai; Zhang, Jun; Gu, Ying; Li, Shaowei; Xia, Ningshao] Xiamen Univ, Sch Publ Hlth, Dept Lab Med,Sch Life Sci, State Key Lab Vaccines Infect Dis,Xiang An Biomed, Xiamen 361102, Peoples R China; [Zhang, Xiuli; Wei, Mingjing; Zhang, Zhigang; Zeng, Yarong; Zou, Feihong; Zhang, Sibo; Wang, Zhiping; Chen, Fentian; Xiong, Hualong; Li, Yufang; Zhou, Lizhi; Li, Tingting; Zheng, Qingbing; Yu, Hai; Zhang, Jun; Gu, Ying; Li, Shaowei; Xia, Ningshao] Xiamen Univ, State Key Lab Mol Vaccinol & Mol Diagnost, Natl Inst Diagnost & Vaccine Dev Infect Dis,Collab, Natl Innovat Platform Ind Educ Integrat Vaccine Re, Xiamen 361102, Peoples R China; [Zhao, Qinjian] Chongqing Med Univ, Coll Pharm, Chongqing 400016, Peoples R China
通信作者：Li, SW; Xia, NS (通讯作者)，Xiamen Univ, Sch Publ Hlth, Dept Lab Med,Sch Life Sci, State Key Lab Vaccines Infect Dis,Xiang An Biomed, Xiamen 361102, Peoples R China.; Zhao, QJ (通讯作者)，Chongqing Med Univ, Coll Pharm, Chongqing 400016, Peoples R China.
来源：JOURNAL OF CONTROLLED RELEASE
ESI学科分类：PHARMACOLOGY & TOXICOLOGY
WOS号：WOS:001172913500001
JCR分区：Q1
影响因子：10.5
年份：2024
卷号：367
期号：
开始页：13
结束页：26
文献类型：Article
关键词：Manganese; Bisphosphonates; Risedronate; Vaccine adjuvant; Tumor immunotherapy
摘要：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 longterm 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 (R). 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.
基金机构：Funds for the Central Universities [20720220004, 20720220006]
基金资助正文：<B>Acknowledgements</B> This study was supported by National Key Research and Develop-ment Program through grants No. 2021YFC2301404, National Natural Science Foundation of China through grants No. 81991491, No.32170942 and No. 32070925, CAMS Innovation Fund for Medical Sciences through grants No. 2019RU022, and the Fundamental Researchr Funds for the Central Universities through grants No. 20720220004 and 20720220006. The authors thank Yaojin Chen for helping in ICP-OES analysis.
