近日，中国科学院上海药物研究所于海军团队实现了超声激活脂质纳米平台用于局部先天免疫刺激和mRNA疫苗治疗癌症。2025年8月25日，《美国化学会志》发表了这一成果。

佐剂整合脂质纳米颗粒（LNP）配方已被广泛研究，通过促进抗原呈递细胞（APCs）的先天免疫刺激来增强mRNA疫苗治疗。然而，这些策略受到佐剂的非特异性和“始终在线”的先天免疫刺激作用的挑战，在很大程度上阻碍了它们的临床转化。

研究组开发了一种新的LNP成分，超声辅助脂质，赋予临床批准的LNP配方具有区域限制的佐剂性。工程超声（US）可激活LNP（ULNP）。通过US触发APCs细胞质DNA传感通路的激活，精确地增强了淋巴结（LN）的先天免疫反应。与传统LNP整合toll样受体佐剂相比，ULNP结合局部US刺激（ULNP + US）不仅增强了ln特异性mRNA转染，还引发了2.5倍的抗原特异性CD8+ T细胞反应，从而抑制了肿瘤的生长。

更重要的是，US可激活的佐剂策略很容易适用于增强肿瘤新抗原编码环状RNA （circRNA）疫苗治疗。将circRNA负载的ULNP （ci-ULNP）与US刺激结合，可引发有效的抗肿瘤T细胞免疫，并完全消除小鼠原位肝肿瘤。综上所述，超声佐剂脂质整合ULNP为肿瘤的时空可调先天免疫刺激和mRNA接种治疗提供了一个平台。

附：英文原文

Title: Ultrasound-Activatable Lipid Nanoplatform for Region-Confined Innate Immune Stimulation and mRNA Vaccination Therapy of Cancer

Author: Fangmin Chen, Siyuan Ren, Lujia Huang, Qilong Wu, Mengfan Li, Shiqin Li, Jing Gao, Yi Lai, Zhixiong Cai, Xiaolong Liu, Wei Tao, Twan Lammers, Zhiai Xu, Haijun Yu

Issue&Volume: August 25, 2025

Abstract: 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+ 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.

DOI: 10.1021/jacs.5c06028

Source: https://pubs.acs.org/doi/abs/10.1021/jacs.5c06028