Liu Chuang, Huang Xiangang, Chen Kok-Siong, Xiong Sihan, Yaremenko Alexey V, Zhen Xueyan, You Xinru, Rossignoli Filippo, Tang Yi, Koo Seyoung, Chen Wei, Kong Na, Xie Tian, Shah Khalid, Tao Wei
Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Center for Stem Cell and Translational Immunotherapy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Nat Nanotechnol. 2025 Aug 11. doi: 10.1038/s41565-025-01980-7.
Daily subcutaneous injections of recombinant interleukin-10 (IL-10) demonstrated encouraging but preliminary efficacy in certain tumour types during early phase clinical trials. However, these antitumour effects were not consistently replicated in larger trials, probably due to insufficient intratumoural recombinant IL-10 accumulation, which ultimately restricted clinical benefit. Here we show that intravenous injections of IL-10 messenger RNA (mRNA) nanoparticles (IL-10-mRNA@NPs) induce potent immune surveillance across diverse preclinical tumour models and mitigate systemic toxicities. In particular, IL-10-mRNA@NPs sustain in situ IL-10 production within tumours, promoting substantial infiltration and proliferation of cytotoxic T cells, activation and maturation of dendritic cells, and an augmented expression of major histocompatibility complex class I molecules in immunosuppressive orthotopic early stage hepatocellular carcinoma tumours. Moreover, in mice with orthotopic middle-to-late-stage hepatocellular carcinoma tumours, combining IL-10-mRNA@NPs with immune checkpoint blockades results in 43% of mice showing complete tumour eradication and a sixfold increase in median survival compared with mice treated with immune checkpoint blockades alone. Furthermore, this combination induces long-lasting antitumour immune memory, conferring 100% protection against tumour rechallenges. The intravenous IL-10-mRNA@NPs strategy may have potential to overcome the challenges associated with recombinant IL-10 in clinical trials across a broad spectrum of immunosuppressive tumours.
在早期临床试验中，每日皮下注射重组白细胞介素10（IL-10）在某些肿瘤类型中显示出令人鼓舞但尚属初步的疗效。然而，这些抗肿瘤作用在更大规模的试验中并未得到一致的重复，这可能是由于肿瘤内重组IL-10积累不足，最终限制了临床获益。在此，我们表明静脉注射IL-10信使核糖核酸（mRNA）纳米颗粒（IL-10-mRNA@NPs）可在多种临床前肿瘤模型中诱导强大的免疫监视并减轻全身毒性。特别是，IL-10-mRNA@NPs可在肿瘤内维持原位IL-10产生，促进细胞毒性T细胞的大量浸润和增殖、树突状细胞的活化和成熟，以及免疫抑制原位早期肝细胞癌肿瘤中主要组织相容性复合体I类分子表达的增加。此外，在原位中晚期肝细胞癌肿瘤小鼠中，将IL-10-mRNA@NPs与免疫检查点阻断剂联合使用，导致43%的小鼠肿瘤完全消除，与单独接受免疫检查点阻断剂治疗的小鼠相比，中位生存期延长了六倍。此外，这种联合诱导持久的抗肿瘤免疫记忆，赋予100%的肿瘤再攻击保护。静脉注射IL-10-mRNA@NPs策略可能有潜力克服在广泛的免疫抑制性肿瘤的临床试验中与重组IL-10相关的挑战。
