Ren Lanfang, Zhao Zeda, Chao Yuqing, Yu Panting, Mei Zhoufang, Du Bing, Cheng Yiyun
Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, 200241, P. R. China.
Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006, P. R. China.
Adv Sci (Weinh). 2025 May;12(17):e2500844. doi: 10.1002/advs.202500844. Epub 2025 Mar 8.
Lipid nanoparticles (LNPs) have been successful in delivering nucleic acids like siRNA and mRNA, but face challenges in protein delivery due to limited protein encapsulation and endosome escape. In this study, a family of LNPs is developed with robust high efficiency in addressing the multiple barriers in cytosolic protein delivery by incorporating clinically approved ionizable lipids into traditional cationic LNPs. The combination of cationic and ionizable lipids enables efficient protein binding and endosomal escape. Optimized LNPs efficiently deliver various proteins, including antibodies, enzymes, toxins, and Cas9 into living cells with reserved functions. Moreover, the designed LNPs show high serum stability during protein delivery, and the serum albumin adsorbed on LNPs facilitates protein delivery via albumin receptor-mediated endocytosis, enabling highly efficient protein delivery in vivo. The optimized LNPs successfully deliver therapeutic proteins such as saporin and interleukin-10 (IL-10) to inhibit tumor growth in several animal models. The IL-10 loaded LNPs enhanced the proliferation and cytotoxicity of T cells and improved the antitumor effect of adoptive transferred OT-1 CD8 T cells to melanoma. This study expands the applications of LNPs for the delivery of biomacromolecules, and the developed LNP formulations have enormous potential for the delivery of protein therapeutics to treat various diseases.
脂质纳米颗粒（LNPs）已成功用于递送诸如siRNA和mRNA等核酸，但由于蛋白质包封率有限和内体逃逸问题，在蛋白质递送方面面临挑战。在本研究中，通过将临床批准的可电离脂质掺入传统阳离子LNPs中，开发了一类在解决胞质蛋白质递送中的多种障碍方面具有强大高效性的LNPs。阳离子脂质和可电离脂质的组合实现了高效的蛋白质结合和内体逃逸。优化后的LNPs能有效地将包括抗体、酶、毒素和Cas9在内的各种蛋白质递送至活细胞中，并保留其功能。此外，所设计的LNPs在蛋白质递送过程中表现出高血清稳定性，吸附在LNPs上的血清白蛋白通过白蛋白受体介导的内吞作用促进蛋白质递送，从而在体内实现高效的蛋白质递送。优化后的LNPs成功地将诸如皂草素和白细胞介素-10（IL-10）等治疗性蛋白质递送至多种动物模型中以抑制肿瘤生长。负载IL-10的LNPs增强了T细胞的增殖和细胞毒性，并改善了过继转移的OT-1 CD8 T细胞对黑色素瘤的抗肿瘤作用。本研究扩展了LNPs在生物大分子递送方面的应用，并且所开发的LNP制剂在递送蛋白质治疗药物以治疗各种疾病方面具有巨大潜力。
