Early View e202503749

Research Article

Atorvastatin-Loaded Mineralized Vaccine Reprograms Endosomal Trafficking to Amplify STING-Driven Cancer Immunotherapy

Yuhan Yang

Department of Pharmaceutics, School of Pharmacy, Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 211198 P.R. China

Both authors contributed equally to this work.

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Wei Long,

Wei Long

Department of Pharmaceutics, School of Pharmacy, Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 211198 P.R. China

Both authors contributed equally to this work.

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Xiangyu Pei,

Xiangyu Pei

Department of Pharmaceutics, School of Pharmacy, Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 211198 P.R. China

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Shangfei Li,

Shangfei Li

Department of Pharmaceutics, School of Pharmacy, Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 211198 P.R. China

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Bowen Fu,

Bowen Fu

Department of Pharmaceutics, School of Pharmacy, Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 211198 P.R. China

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Hao Zhai,

Hao Zhai

Department of Pharmaceutics, School of Pharmacy, Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 211198 P.R. China

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Xiaoyi Zhang,

Xiaoyi Zhang

Department of Pharmaceutics, School of Pharmacy, Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 211198 P.R. China

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Ying Wan,

Ying Wan

Department of Pharmaceutics, School of Pharmacy, Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 211198 P.R. China

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Prof. Yayun Peng,

Corresponding Author

Prof. Yayun Peng

[email protected]

orcid.org/0000-0002-1301-6111

Department of Pharmaceutics, School of Pharmacy, Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 211198 P.R. China

E-mail: [email protected]; [email protected]

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Ting Cai,

Corresponding Author

Ting Cai

[email protected]

orcid.org/0000-0001-7510-9295

Department of Pharmaceutics, School of Pharmacy, Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 211198 P.R. China

E-mail: [email protected]; [email protected]

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Yuhan Yang,

Yuhan Yang

Department of Pharmaceutics, School of Pharmacy, Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 211198 P.R. China

Both authors contributed equally to this work.

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Wei Long,

Wei Long

Department of Pharmaceutics, School of Pharmacy, Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 211198 P.R. China

Both authors contributed equally to this work.

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Xiangyu Pei,

Xiangyu Pei

Department of Pharmaceutics, School of Pharmacy, Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 211198 P.R. China

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Shangfei Li,

Shangfei Li

Department of Pharmaceutics, School of Pharmacy, Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 211198 P.R. China

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Bowen Fu,

Bowen Fu

Department of Pharmaceutics, School of Pharmacy, Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 211198 P.R. China

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Hao Zhai,

Hao Zhai

Department of Pharmaceutics, School of Pharmacy, Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 211198 P.R. China

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Xiaoyi Zhang,

Xiaoyi Zhang

Department of Pharmaceutics, School of Pharmacy, Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 211198 P.R. China

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Ying Wan,

Ying Wan

Department of Pharmaceutics, School of Pharmacy, Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 211198 P.R. China

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Prof. Yayun Peng,

Corresponding Author

Prof. Yayun Peng

[email protected]

orcid.org/0000-0002-1301-6111

Department of Pharmaceutics, School of Pharmacy, Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 211198 P.R. China

E-mail: [email protected]; [email protected]

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Ting Cai,

Corresponding Author

Ting Cai

[email protected]

orcid.org/0000-0001-7510-9295

Department of Pharmaceutics, School of Pharmacy, Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 211198 P.R. China

E-mail: [email protected]; [email protected]

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First published: 23 July 2025

https://doi.org/10.1002/anie.202503749

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Graphical Abstract

A biomineralized nanovaccine (OVA-ATV@MnO₂) spatiotemporally co-delivers and releases tumor antigen, atorvastatin, and Mn adjuvants in dendritic cells. Atorvastatin reprograms endosomal trafficking to delay lysosomal degradation, enhancing antigen cross-presentation via MHC-I, while Mn²⁺ activates the cGAS-STING pathway, amplifying dendritic cell maturation and antitumor T-cell responses. This dual-action strategy achieves potent tumor regression, suppresses metastasis, and establishes durable anticancer immunity.

Abstract

Dendritic cell (DC)-targeted nanovaccines offer great promise for cancer immunotherapy but are severely limited by premature lysosomal degradation of antigens, which reduces cross-presentation efficacy. Here, we report a facile yet effective biomineralization strategy to construct nanovaccine (OVA-ATV@MnO₂) that co-delivers ovalbumin (OVA) and atorvastatin (ATV) within MnO₂ matrix. The ATV-mediated nanovaccine reprograms endosomal trafficking by inhibiting the mevalonate (MVA) pathway, thereby delaying endosomal maturation and preventing antigen diversion to degradative lysosomes. This intervention significantly enhances antigen preservation and MHC-I presentation in DCs. Simultaneously, the MnO₂ framework not only stabilizes the vaccine nanostructure but also releases Mn²⁺ ions as an adjuvant to potently activate the cGAS-STING pathway, amplifying DC maturation and antitumor T-cell priming. In vivo studies demonstrate that the nanovaccine induces robust tumor regression, suppresses metastasis, and establishes durable prophylactic immunity. By synergistically rewiring intracellular antigen trafficking and amplifying STING-mediated immune activation, this mineralized vaccine platform provides a transformative strategy for precise cancer immunotherapy.

Conflict of Interests

The authors declare no conflict of interest.

Open Research

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Supporting Information

References

1I. Mellman, G. Coukos, G. Dranoff, Nature 2011, 480, 480–489.
10.1038/nature10673
CAS PubMed Web of Science® Google Scholar
2J. Nam, S. Son, K. S. Park, W. Zou, L. D. Shea, J. J. Moon, Nat. Rev. Mater. 2019, 4, 398–414.
10.1038/s41578-019-0108-1
Web of Science® Google Scholar
3W. Jiang, Y. Wang, J. A. Wargo, F. F. Lang, B. Y. S. Kim, Nat. Nanotechnol. 2021, 16, 6–15.
10.1038/s41565-020-00817-9
CAS PubMed Web of Science® Google Scholar
4Y. Yang, Y. Yu, H. Chen, X. Meng, W. Ma, M. Yu, Z. Li, C. Li, H. Liu, X. Zhang, H. Xiao, Z. Yu, ACS Nano 2020, 14, 13536–13547.
10.1021/acsnano.0c05541
CAS PubMed Web of Science® Google Scholar
5L. Yu, Z. Wang, Z. Mo, B. Zou, Y. Yang, R. Sun, W. Ma, M. Yu, S. Zhang, Z. Yu, Acta Pharm. Sin. B 2021, 11, 2004–2015.
10.1016/j.apsb.2021.02.001
CAS PubMed Web of Science® Google Scholar
6X. Tan, J. Huang, Y. Wang, S. He, L. Jia, Y. Zhu, K. Pu, Y. Zhang, X. Yang, Angew. Chem. Int. Ed. 2021, 60, 14051–14059.
10.1002/anie.202102703
CAS PubMed Web of Science® Google Scholar
7S. Peng, A. Lin, A. Jiang, C. Zhang, J. Zhang, Q. Cheng, P. Luo, Y. Bai, Mol. Cancer 2024, 23, 58.
10.1186/s12943-024-01972-6
CAS PubMed Web of Science® Google Scholar
8S. H. van der Burg, R. Arens, F. Ossendorp, T. van Hall, C. J. Melief, Nat. Rev. Cancer 2016, 16, 219–233.
10.1038/nrc.2016.16
CAS PubMed Web of Science® Google Scholar
9M. Saxena, S. H. van der Burg, C. J. M. Melief, N. Bhardwaj, Nat. Rev. Cancer 2021, 21, 360–378.
10.1038/s41568-021-00346-0
CAS PubMed Web of Science® Google Scholar
10Z. Hu, P. A. Ott, C. J. Wu, Nat. Rev. Immunol. 2018, 18, 168–182.
10.1038/nri.2017.131
CAS PubMed Web of Science® Google Scholar
11S. J. Patel, N. E. Sanjana, R. J. Kishton, A. Eidizadeh, S. K. Vodnala, M. Cam, J. J. Gartner, L. Jia, S. M. Steinberg, T. N. Yamamoto, A. S. Merchant, G. U. Mehta, A. Chichura, O. Shalem, E. Tran, R. Eil, M. Sukumar, E. P. Guijarro, C. P. Day, P. Robbins, S. Feldman, G. Merlino, F. Zhang, N. P. Restifo, Nature 2017, 548, 537–542.
10.1038/nature23477
CAS PubMed Web of Science® Google Scholar
12S. Jhunjhunwala, C. Hammer, L. Delamarre, Nat. Rev. Cancer 2021, 21, 298–312.
10.1038/s41568-021-00339-z
CAS PubMed Web of Science® Google Scholar
13I. Cebrian, G. Visentin, N. Blanchard, M. Jouve, A. Bobard, C. Moita, J. Enninga, L. F. Moita, S. Amigorena, A. Savina, Cell 2011, 147, 1355–1368.
10.1016/j.cell.2011.11.021
CAS PubMed Web of Science® Google Scholar
14Y. Xia, Y. Xie, Z. Yu, H. Xiao, G. Jiang, X. Zhou, Y. Yang, X. Li, M. Zhao, L. Li, M. Zheng, S. Han, Z. Zong, X. Meng, H. Deng, H. Ye, Y. Fa, H. Wu, E. Oldfield, X. Hu, W. Liu, Y. Shi, Y. Zhang, Cell. 2018, 175, 1059–1073.
10.1016/j.cell.2018.08.070
CAS PubMed Web of Science® Google Scholar
15P. J. Mullen, R. Yu, J. Longo, M. C. Archer, L. Z. Penn, Nat. Rev. Cancer 2016, 16, 718–731.
10.1038/nrc.2016.76
CAS PubMed Web of Science® Google Scholar
16T. W. Chen, F. F. Yin, Y. M. Yuan, D. X. Guan, E. Zhang, F. K. Zhang, H. Jiang, N. Ma, J. J. Wang, Q. Z. Ni, L. Qiu, J. Feng, X. L. Zhang, Y. Bao, K. Wang, S. Q. Cheng, X. F. Wang, X. Wang, J. J. Li, D. Xie, Nat. Commun. 2019, 10, 2510.
10.1038/s41467-019-10364-0
PubMed Web of Science® Google Scholar
17S. M. El-Refai, J. D. Brown, S. M. Arnold, E. P. Black, M. Leggas, J. C. Talbert, JCO Clin. Cancer Inform. 2017, 1, 1–12.
10.1200/CCI.17.00010
PubMed Google Scholar
18J. Jurczyluk, M. A. Munoz, O. P. Skinner, R. C. Chai, N. Ali, U. Palendira, J. M. Quinn, A. Preston, S. G. Tangye, A. J. Brown, E. Argent, J. B. Ziegler, S. Mehr, M. J. Rogers, Immunol. Cell Biol. 2016, 94, 994–999.
10.1038/icb.2016.58
CAS PubMed Web of Science® Google Scholar
19F. Bonnet, P. Poulizac, J. P. Joseph, Lancet 2017, 389, 1097–1098.
10.1016/S0140-6736(17)30712-2
Web of Science® Google Scholar
20O. P. Joffre, E. Segura, A. Savina, S. Amigorena, Nat. Rev. Immunol. 2012, 12, 557–569.
10.1038/nri3254
CAS PubMed Web of Science® Google Scholar
21A. O. Kamphorst, A. Wieland, T. Nasti, S. Yang, R. Zhang, D. L. Barber, B. T. Konieczny, C. Z. Daugherty, L. Koenig, K. Yu, G. L. Sica, A. H. Sharpe, G. J. Freeman, B. R. Blazar, L. A. Turka, T. K. Owonikoko, R. N. Pillai, S. S. Ramalingam, K. Araki, R. Ahmed, Science 2017, 355, 1423–1427.
10.1126/science.aaf0683
CAS PubMed Web of Science® Google Scholar
22X. Sun, X. Zhou, X. Shi, O. A. Abed, X. An, Y. L. Lei, J. J. Moon, Nat. Biomed. Eng. 2024, 8, 1073–1091.
10.1038/s41551-024-01221-7
CAS PubMed Web of Science® Google Scholar
23M. Lv, M. Chen, R. Zhang, W. Zhang, C. Wang, Y. Zhang, X. Wei, Y. Guan, J. Liu, K. Feng, M. Jing, X. Wang, Y. C. Liu, Q. Mei, W. Han, Z. Jiang, Cell Res. 2020, 30, 966–979.
10.1038/s41422-020-00395-4
CAS PubMed Web of Science® Google Scholar
24C. Wang, L. Zhong, J. Xu, Q. Zhuang, F. Gong, X. Chen, H. Tao, C. Hu, F. Huang, N. Yang, J. Li, Q. Zhao, X. Sun, Y. Huo, Q. Chen, Y. Zhao, R. Peng, Z. Liu, Nat. Biomed. Eng. 2024, 8, 561–568.
10.1038/s41551-024-01191-w
CAS PubMed Web of Science® Google Scholar
25X. Sun, Y. Zhang, J. Li, K. S. Park, K. Han, X. Zhou, Y. Xu, J. Nam, J. Xu, X. Shi, L. Wei, Y. L. Lei, J. J. Moon, Nat. Nanotechnol. 2021, 16, 1260–1270.
10.1038/s41565-021-00962-9
CAS PubMed Web of Science® Google Scholar
26L. Wang-Bishop, B. R. Kimmel, V. M. Ngwa, M. Z. Madden, J. J. Baljon, D. C. Florian, A. Hanna, L. E. Pastora, T. L. Sheehy, A. J. Kwiatkowski, M. Wehbe, X. Wen, K. W. Becker, K. M. Garland, J. A. Schulman, D. Shae, D. Edwards, M. M. Wolf, R. Delapp, P. P. Christov, K. E. Beckermann, J. M. Balko, W. K. Rathmell, J. C. Rathmell, J. Chen, J. T. Wilson, Sci. Immunol. 2023, 8, eadd1153.
10.1126/sciimmunol.add1153
CAS PubMed Web of Science® Google Scholar
27X. Zhang, X. C. Bai, Z. J. Chen, Immunity 2020, 53, 43–53.
10.1016/j.immuni.2020.05.013
CAS PubMed Web of Science® Google Scholar
28K. Zhang, C. Qi, K. Cai, Adv. Mater. 2023, 35, e2205409.
10.1002/adma.202205409
CAS PubMed Web of Science® Google Scholar
29Q. Li, Z. Dong, Z. Cao, H. Lei, C. Wang, Y. Hao, L. Feng, Z. Liu, ACS Nano 2023, 17, 10496–10510.
10.1021/acsnano.3c01404
CAS PubMed Web of Science® Google Scholar
30X. Ding, J. Zhang, S. Wan, X. Wang, Z. Wang, K. Pu, M. Wang, Y. Cao, L. Weng, H. Zhu, F. Peng, J. Chao, R. Pei, D. T. Leong, L. Wang, Nat. Nanotechnol. 2025, 20, S41565.
10.1038/s41565-024-01783-2
Web of Science® Google Scholar
31S. Yao, B. Jin, Z. Liu, C. Shao, R. Zhao, X. Wang, R. Tang, Adv. Mater. 2017, 29, 1605903.
10.1002/adma.201605903
CAS Web of Science® Google Scholar
32H. Zhao, J. Xu, Y. Li, X. Guan, X. Han, Y. Xu, H. Zhou, R. Peng, J. Wang, Z. Liu, ACS Nano 2019, 13, 13127–13135.
10.1021/acsnano.9b05974
CAS PubMed Web of Science® Google Scholar
33Y. Wang, Y. Xie, J. Luo, M. Guo, X. Hu, X. Chen, Z. Chen, X. Lu, L. Mao, K. Zhang, L. Wei, Y. Ma, R. Wang, J. Zhou, C. He, Y. Zhang, Y. Zhang, S. Chen, L. Shen, Y. Chen, N. Qiu, Y. Liu, Y. Cui, G. Liao, Y. Liu, C. Chen, Nano Today 2021, 38, 101139.
10.1016/j.nantod.2021.101139
CAS PubMed Web of Science® Google Scholar
34Z. Deng, M. Xi, C. Zhang, X. Wu, Q. Li, C. Wang, H. Fang, G. Sun, Y. Zhang, G. Yang, Z. Liu, ACS Nano 2023, 17, 4495–4506.
10.1021/acsnano.2c10352
CAS PubMed Web of Science® Google Scholar
35S. T. Reddy, A. J. van der Vlies, E. Simeoni, V. Angeli, G. J. Randolph, C. P. O'Neil, L. K. Lee, M. A. Swartz, J. A. Hubbell, Nat. Biotechnol. 2007, 25, 1159–1164.
10.1038/nbt1332
CAS PubMed Web of Science® Google Scholar
36G. Zhu, G. M. Lynn, O. Jacobson, K. Chen, Y. Liu, H. Zhang, Y. Ma, F. Zhang, R. Tian, Q. Ni, S. Cheng, Z. Wang, N. Lu, B. C. Yung, Z. Wang, L. Lang, X. Fu, A. Jin, I. D. Weiss, H. Vishwasrao, G. Niu, H. Shroff, D. M. Klinman, R. A. Seder, X. Chen, Nat. Commun. 2017, 8, 1954.
10.1038/s41467-017-02191-y
PubMed Web of Science® Google Scholar
37Y. Peng, C. Ye, R. Yan, Y. Lei, D. Ye, H. Hong, T. Cai, ACS Appl. Mater. Interfaces 2019, 11, 46637–46644.
10.1021/acsami.9b18807
CAS PubMed Web of Science® Google Scholar
38F. Jia, W. Huang, Y. Yin, Y. Jiang, Q. Yang, H. Huang, G. Nie, H. Wang, Adv. Funct. Mater. 2022, 33, 2204636.
10.1002/adfm.202204636
Web of Science® Google Scholar
39L. Zitvogel, L. Galluzzi, O. Kepp, M. J. Smyth, G. Kroemer, Nat. Rev. Immunol. 2015, 15, 405–414.
10.1038/nri3845
CAS PubMed Web of Science® Google Scholar
40R. Zhang, C. Wang, Y. Guan, X. Wei, M. Sha, M. Yi, M. Jing, M. Lv, W. Guo, J. Xu, Y. Wan, X. M. Jia, Z. Jiang, Cell Mol. Immunol. 2021, 18, 1222–1234.
10.1038/s41423-021-00669-w
CAS PubMed Web of Science® Google Scholar
41C. Liu, X. Liu, X. Xiang, X. Pang, S. Chen, Y. Zhang, E. Ren, L. Zhang, X. Liu, P. Lv, X. Wang, W. Luo, N. Xia, X. Chen, G. Liu, Nat. Nanotechnol. 2022, 17, 531–540.
10.1038/s41565-022-01098-0
CAS PubMed Web of Science® Google Scholar
42P. C. Tumeh, C. L. Harview, J. H. Yearley, I. P. Shintaku, E. J. Taylor, L. Robert, B. Chmielowski, M. Spasic, G. Henry, V. Ciobanu, A. N. West, M. Carmona, C. Kivork, E. Seja, G. Cherry, A. J. Gutierrez, T. R. Grogan, C. Mateus, G. Tomasic, J. A. Glaspy, R. O. Emerson, H. Robins, R. H. Pierce, D. A. Elashoff, C. Robert, A. Ribas, Nature 2014, 515, 568–571.
10.1038/nature13954
CAS PubMed Web of Science® Google Scholar
43E. Hui, J. Cheung, J. Zhu, X. Su, M. J. Taylor, H. A. Wallweber, D. K. Sasmal, J. Huang, J. M. Kim, I. Mellman, R. D. Vale, Science 2017, 355, 1428–1433.
10.1126/science.aaf1292
CAS PubMed Web of Science® Google Scholar
44S. M. Lewis, A. Williams, S. C. Eisenbarth, Sci. Immunol. 2019, 4, eaau6085.
10.1126/sciimmunol.aau6085
CAS PubMed Web of Science® Google Scholar
45S. Wang, D. Z. Ni, H. Yue, N. N. Luo, X. B. Xi, Y. G. Wang, M. Shi, W. Wei, G. H. Ma, Small 2018, 14, e1704272.
10.1002/smll.201704272
PubMed Web of Science® Google Scholar
46G. Chong, R. Su, J. Gu, Y. Yang, T. Zhang, J. Zang, Y. Zhao, X. Zheng, Y. Liu, S. Ruan, R. He, W. Yin, Y. Li, H. Dong, Y. Li, Chem. Eng. J. 2022, 435, 134993.
10.1016/j.cej.2022.134993
CAS Web of Science® Google Scholar
47P. Bousso, Nat. Rev. Immunol. 2008, 8, 675–684.
10.1038/nri2379
CAS PubMed Web of Science® Google Scholar
48X. Sun, X. Huang, K. S. Park, X. Zhou, A. A. Kennedy, C. D. Pretto, Q. Wu, Z. Wan, Y. Xu, W. Gong, J. Z. Sexton, A. W. Tai, Y. L. Lei, J. J. Moon, ACS Nano 2024, 18, 10439–10453.
10.1021/acsnano.3c11374
CAS PubMed Web of Science® Google Scholar
49Y. Sheng, Z. Li, X. Lin, L. Wang, H. Zhu, Z. Su, S. Zhang, J. Control. Release 2024, 368, 275–289.
10.1016/j.jconrel.2024.02.027
CAS PubMed Web of Science® Google Scholar

Early View

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e202503749

Atorvastatin-Loaded Mineralized Vaccine Reprograms Endosomal Trafficking to Amplify STING-Driven Cancer Immunotherapy

Graphical Abstract

Abstract

Conflict of Interests

Open Research

Data Availability Statement

Supporting Information

References

References

Information

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Atorvastatin-Loaded Mineralized Vaccine Reprograms Endosomal Trafficking to Amplify STING-Driven Cancer Immunotherapy

Graphical Abstract

Abstract

Conflict of Interests

Open Research

Data Availability Statement

Supporting Information

References

References

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