Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, PR China; School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026, PR China.
College of Chemistry, Jilin University, Changchun, 130012, PR China.
Biomaterials. 2025 Mar;314:122870. doi: 10.1016/j.biomaterials.2024.122870. Epub 2024 Oct 3.
Cationic oncolytic polypeptides have gained increasing attention owing to their ability to directly lyse cancer cells and activate potent antitumor immunity. However, the low tumor cell selectivity and inherent toxicity induced by positive charges of oncolytic polypeptides hinder their systemic application. Herein, a tumor microenvironment-responsive nanoparticle (DNP) is developed by the self-assembly of a cationic oncolytic polypeptide (PLP) with a pH-sensitive anionic polypeptide via electrostatic interactions. After the formation of DNP, the positive charges of PLP are shielded. DNPs can keep stable in physiological conditions (pH 7.4) but respond to acidic tumor microenvironment (pH 6.8) to release oncolytic PLP. As a result, DNPs evoke potent immunogenic cell death by disrupting cell membranes, damaging mitochondria and increasing intracellular levels of reactive oxygen species. In vivo results indicate that DNPs significantly improve the biocompatibility of PLP, and inhibit tumor growth, recurrence and metastasis by direct oncolysis and activation of antitumor immune responses. In summary, these results indicate that pH-sensitive DNPs represent a prospective strategy to improve the tumor selectivity and biosafety of cationic polymers for oncolytic immunotherapy.
阳离子溶瘤多肽由于能够直接裂解癌细胞并激活有效的抗肿瘤免疫而受到越来越多的关注。然而，溶瘤多肽的正电荷导致其对肿瘤细胞的选择性低和固有毒性，这限制了它们的系统应用。在此，通过静电相互作用将阳离子溶瘤多肽（PLP）与 pH 敏感的阴离子多肽自组装成一种肿瘤微环境响应性纳米颗粒（DNP）。形成 DNP 后，PLP 的正电荷被屏蔽。DNP 在生理条件（pH7.4）下保持稳定，但能响应酸性肿瘤微环境（pH6.8）释放溶瘤 PLP。结果，DNP 通过破坏细胞膜、损伤线粒体和增加细胞内活性氧水平来引发强烈的免疫原性细胞死亡。体内结果表明，DNP 显著提高了 PLP 的生物相容性，并通过直接溶瘤和激活抗肿瘤免疫反应来抑制肿瘤生长、复发和转移。总之，这些结果表明 pH 敏感的 DNP 为提高阳离子聚合物的肿瘤选择性和生物安全性以用于溶瘤免疫治疗提供了一种有前景的策略。
