Polymeric nanoparticle gel for intracellular mRNA delivery and immunological reprogramming of tumors.
Polymeric nanoparticle gel for intracellular mRNA delivery and immunological reprogramming of tumors.
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DOI：
10.1016/j.biomaterials.2023.122185
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发表时间：
2023-05
期刊：
影响因子：
14
通讯作者：
Sarah Y. Neshat;Chun Hei Ryan Chan;Jawaun J. Harris;Osamah M. Zmily;S. Est-Witte;J. Karlsson;
中科院分区：
文献类型：
--
作者：
Sarah Y. Neshat;Chun Hei Ryan Chan;Jawaun J. Harris;Osamah M. Zmily;S. Est-Witte;J. Karlsson;
以诱导肿瘤持续消退为目标的免疫肿瘤学治疗已引起人们的极大兴趣，但临床结果表明，需要改进和广泛应用的方法。一种无抗原的癌症免疫治疗方法可以刺激免疫系统招募淋巴细胞并产生免疫刺激因子，而不需要事先知道新的抗原，而局部给药降低了全身毒性的风险。为了改善肿瘤细胞与细胞毒性淋巴细胞之间的相互作用，设计了一种基因传递纳米颗粒平台，通过诱导肿瘤相关抗原提呈细胞(TAPC)激活抗肿瘤细胞毒性淋巴细胞，使肿瘤微环境(TME)具有更强的免疫刺激作用。合成了可生物降解的亲脂性聚(β-氨基酯)(PBAE)纳米粒子，并将其用于共传递编码信号2共刺激分子(4-1BBL)和信号3免疫刺激细胞因子(IL-12)的mRNA构建体，以及基于核酸的免疫调节佐剂。纳米颗粒与热敏性嵌段共聚物结合，在注射部位凝胶化，使NP在肿瘤局部滞留。重编程纳米颗粒凝胶与免疫检查点阻断(ICB)协同作用，诱导肿瘤消退和清除，以及对远处肿瘤再攻击的抵抗。体内和体内研究表明，纳米颗粒增加了免疫刺激细胞因子的产生和免疫细胞的招募。通过可注射的热响应凝胶将包裹免疫刺激剂和佐剂的纳米颗粒注射到肿瘤内，作为一种可供广泛患者使用的免疫肿瘤治疗方法，具有巨大的翻译潜力。
Immuno-oncology therapies have been of great interest with the goal of inducing sustained tumor regression, but clinical results have demonstrated the need for improved and widely applicable methods. An antigen-free method of cancer immunotherapy can stimulate the immune system to recruit lymphocytes and produce immunostimulatory factors without prior knowledge of neoantigens, while local delivery reduces the risk of systemic toxicity. To improve the interactions between tumor cells and cytotoxic lymphocytes, a gene delivery nanoparticle platform was engineered to reprogram the tumor microenvironment (TME)in situto be more immunostimulatory by inducing tumor-associated antigen-presenting cells (tAPCs) to activate cytotoxic lymphocytes against the tumor. Biodegradable, lipophilic poly (beta-amino ester) (PBAE) nanoparticles were synthesized and used to co-deliver mRNA constructs encoding a signal 2 co-stimulatory molecule (4-1BBL) and a signal 3 immuno-stimulatory cytokine (IL-12), along with a nucleic acid-based immunomodulatory adjuvant. Nanoparticles are combined with a thermoresponsive block copolymer for gelation at the injection site for local NP retention at the tumor. The reprogramming nanoparticle gel synergizes with immune checkpoint blockade (ICB) to induce tumor regression and clearance in addition to resistance to tumor rechallenge at a distant site.In vitroandin vivostudies reveal increases in immunostimulatory cytokine production and recruitment of immune cells as a result of the nanoparticles. Intratumoral injection of nanoparticles encapsulating mRNA encoding immunostimulatory agents and adjuvants via an injectable thermoresponsive gel has great translational potential as an immuno-oncology therapy that can be accessible to a wide range of patients.