Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, P. R. China.
Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, P. R. China.
Acta Biomater. 2022 Sep 15;150:353-366. doi: 10.1016/j.actbio.2022.07.022. Epub 2022 Jul 16.
Immunosuppressive tumor microenvironment (ITM), poor immunogenicity, and low tumor penetration markedly reduce the capability of tumor immunotherapy. To address these challenges, we successfully engineered acidity-triggered nanoparticles (NPs) with size reduction and charge switchable features to boost tumor immunotherapy based on indoleamine 2,3-dioxygenase 1 siRNA (IDO1 siRNA) and immunogenic cell death (ICD). The NPs significantly augmented tumor penetrating ability and improved cellular uptake via the detachment of 2,3-dimethylmaleic anhydride-grafted poly(ethylene glycol)-poly(L-lysine) copolymer (mPEG-PLL-DMA, PLM) from large-sized NPs with a negative charge. Subsequently, the NPs with a positive charge and small size rapidly escaped from the lysosomes and released mitoxantrone (MIT) and IDO1 siRNA. The antitumor immune response of IDO1 siRNA and MIT provided good antitumor capability by enhancing DC maturation, improving the number of CTLs, and downregulating the level of Tregs in tumor tissues. In summary, the results demonstrated that charge-switchable NPs based on the blockage of the IDO1 pathway and ICD activation induce an efficient antitumor immune response, thus showing high potential for treating primary/distant tumors and reducing metastasis. STATEMENT OF SIGNIFICANCE: Acidity-triggered nanoparticles (NPs) with size reduction and charge reversal to boost tumor immunotherapy based on indoleamine 2,3-dioxygenase 1 siRNA (IDO1 siRNA) and immunogenic cell death (ICD) were engineered. NPs augmented tumor penetrating ability and improved cellular uptake through the detachment of mPEG-PLL-DMA (PLM) from the large-sized MIT/siR-PLM/PPA NPs with negative charge to expose miniature and positively charged MIT/siR-PPA NPs. The NPs rapidly escaped from the lysosome and sequentially released mitoxantrone (MIT) and IDO1 siRNA. The antitumor synergistic effect of inhibiting the IDO1 pathway by IDO1 siRNA and inducing ICD by MIT provided good antitumor capability by enhancing DC maturation, improving the number of CTLs, and downregulating the level of Tregs in tumor tissues. Thus, the NPs showed a promising pathway against aggressive and difficult-to-treat cancers.
免疫抑制性肿瘤微环境（ITM）、低免疫原性和肿瘤穿透性差极大地降低了肿瘤免疫治疗的能力。为了解决这些挑战，我们成功地设计了具有酸度触发的纳米颗粒（NPs），具有尺寸减小和电荷可切换的特性，可基于吲哚胺 2,3-双加氧酶 1 siRNA（IDO1 siRNA）和免疫原性细胞死亡（ICD）增强肿瘤免疫治疗。NPs 通过从带负电荷的大尺寸 NPs 上脱离 2,3-二甲基马来酸接枝的聚乙二醇-聚（L-赖氨酸）共聚物（mPEG-PLL-DMA，PLM），显著增强了肿瘤穿透能力并提高了细胞摄取率。随后，带正电荷和小尺寸的 NPs 迅速从溶酶体中逃逸，并释放米托蒽醌（MIT）和 IDO1 siRNA。IDO1 siRNA 和 MIT 提供的抗肿瘤免疫反应通过增强 DC 成熟、提高 CTL 数量和下调肿瘤组织中 Tregs 的水平提供了良好的抗肿瘤能力。总之，结果表明，基于阻断 IDO1 途径和激活 ICD 的电荷可切换 NPs 诱导有效的抗肿瘤免疫反应，因此具有治疗原发性/远处肿瘤和减少转移的巨大潜力。
基于吲哚胺 2,3-双加氧酶 1 siRNA（IDO1 siRNA）和免疫原性细胞死亡（ICD）的大小减小和电荷反转的酸度触发纳米颗粒（NPs）被工程化用于增强肿瘤免疫治疗。NPs 通过带负电荷的大尺寸 MIT/siR-PLM/PPA NPs 上的 mPEG-PLL-DMA（PLM）的脱离，增强了肿瘤穿透能力并提高了细胞摄取率，从而暴露了微小的带正电荷的 MIT/siR-PPA NPs。NPs 迅速从溶酶体中逃逸，并顺序释放米托蒽醌（MIT）和 IDO1 siRNA。IDO1 siRNA 通过抑制 IDO1 途径和 MIT 通过诱导 ICD 的抗肿瘤协同作用通过增强 DC 成熟、提高 CTL 数量和下调肿瘤组织中 Tregs 的水平提供了良好的抗肿瘤能力。因此，NPs 为治疗侵袭性和难治性癌症提供了一种很有前途的途径。
