Ultrasound-Activatable Lipid Nanoplatform for Region-Confined Innate Immune Stimulation and mRNA Vaccination Therapy of Cancer
Adjuvant-integrated lipid nanoparticle (LNP) formulations have been extensively investigated to potentiate mRNA vaccine therapy by promoting innate immune stimulation in antigen-presenting cells (APCs). However, these strategies are challenged by the non-specific and "always on" innate immunostimulatory effects of adjuvants, largely impeding their clinical translation. In this study, we developed a novel LNP component, sono-adjuvant lipid, to endow clinically approved LNP formulations with region-confined adjuvanticity. The engineered ultrasound (US)-activatable LNP (ULNP) precisely boosted innate immune responses in the lymph nodes (LN) through US-triggered activation of the cytosolic DNA-sensing pathways in APCs. Compared to conventional LNP integrating toll-like receptor adjuvant, the combination of ULNP with localized US stimulation (ULNP + US) not only enhanced LN-specific mRNA transfection but also elicited 2.5-fold higher antigen-specific CD8<sup>+</sup> T cell responses to inhibit established tumor growth. More importantly, the US-activatable adjuvanting strategy was readily applicable to potentiate tumor neoantigen-encoding circular RNA (circRNA) vaccine therapy. Combining circRNA-loaded ULNP (ci-ULNP) with US stimulation elicited potent antitumor T cell immunity and completely eliminated orthotopic liver tumors in mice. Overall, the sono-adjuvant lipid-integrated ULNP offered a robust platform for spatiotemporally tunable innate immune stimulation and mRNA vaccination therapy of cancer.
Authors
- Haijun Yu (ORCID: https://orcid.org/0000-0002-3398-0880)
- Siyuan Ren (ORCID: https://orcid.org/0009-0008-2555-2713)
- Qilong Wu
- Zhixiong Cai (ORCID: https://orcid.org/0000-0002-6458-870X)
- Shiqin Li
- Lujia Huang (ORCID: https://orcid.org/0000-0002-9574-9174)
- Fangmin Chen (ORCID: https://orcid.org/0009-0002-9613-7898)
- Twan Lammers (ORCID: https://orcid.org/0000-0002-1090-6805)
- Jing Gao (ORCID: https://orcid.org/0000-0003-0357-570X)
- Xiaolong Liu (ORCID: https://orcid.org/0000-0002-3096-4981)
- Zhiai Xu (ORCID: https://orcid.org/0000-0002-4391-2507)
- Wei Tao (ORCID: https://orcid.org/0000-0002-4277-3728)
- Mengfan Li (ORCID: https://orcid.org/0009-0009-5017-4280)
- Yi Lai (ORCID: https://orcid.org/0000-0002-2653-4348)
Institutions
- Brigham and Women's Hospital (US)
- Fujian Medical University (CN)
- Nanjing University of Chinese Medicine (CN)
- Harvard University (US)
- Jilin University (CN)
- Chinese Academy of Sciences (CN)
- Xinjiang Institute of Materia Medica (CN)
- Theranostics (New Zealand) (NZ)
- Shanghai Institute of Materia Medica (CN)
- Mengchao Hepatobiliary Hospital (CN)
- Jilin Medical University (CN)
- State Key Laboratory of Chemical Engineering (CN)
- University of Chinese Academy of Sciences (CN)
- East China Normal University (CN)
- RWTH Aachen University (DE)
Publication Details
- Journal
- Journal of the American Chemical Society
- Published
- 2025-08-25
- DOI
- https://doi.org/10.1021/jacs.5c06028
- Citations
- 3
- Primary Topic
- RNA Interference and Gene Delivery
- Type
- article
- Field-Weighted Citation Impact
- 2.42
Funders
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- Ministry of Science and Technology of the People's Republic of China
- Science and Technology Commission of Shanghai Municipality
- State Key Laboratory of Drug Research