Biodegradable lipophilic polymeric mRNA nanoparticles for ligand-free targeting of splenic dendritic cells for cancer vaccination.
Biodegradable lipophilic polymeric mRNA nanoparticles for ligand-free targeting of splenic dendritic cells for cancer vaccination.
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DOI：
10.1073/pnas.2301606120
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发表时间：
2023-06-27
影响因子：
11.1
通讯作者：
Green, Jordan J.
中科院分区：
文献类型：
--
作者：
Ben-Akiva, Elana;Karlsson, Johan;Hemmati, Shayan;Yu, Hongzhe;Tzeng, Stephany Y.;Pardoll, Drew M.;Green, Jordan J.
树突状细胞（Dendritic cells，DC）是医学中的主要力量，具有诱导抗原特异性免疫应答的能力。然而，DC的转染是具有挑战性的，并且当前基于纳米颗粒（NP）的递送系统在促进全身施用后组织介导的递送至淋巴器官方面的成功有限。我们报道了可生物降解的聚合物纳米载体的设计，其能够在系统施用后将靶向mRNA递送至脾DC而不需要靶向配体。我们还证明了佐剂沿着与mRNA的共递送触发DC的共刺激信号传导以激活抗原特异性CD 8 + T细胞。NP设计能够在多种鼠肿瘤模型中实现稳健的抗肿瘤免疫应答。这项技术是一项进步，它验证了全身递送的基于聚合物mRNA的癌症疫苗具有广泛的应用。基于纳米颗粒（NP）的mRNA癌症疫苗有望实现个性化癌症治疗。为了推进该技术，需要用于有效细胞内递送至抗原呈递细胞的递送制剂。我们开发了一类具有四聚体结构的生物可还原亲脂性聚（β-氨基酯）纳米载体。该平台对mRNA序列是不可知的，具有一步自组装，允许递送多种抗原编码mRNA以及共递送基于核酸的佐剂。我们研究了NP介导的mRNA递送到树突状细胞（DC）的结构-功能关系，并确定了聚合物结构的脂质亚基是至关重要的。静脉内给药后，工程化的NP设计促进靶向递送至脾脏和优先转染DC，而不需要用靶向配体进行表面功能化。用共递送编码抗原的mRNA和toll样受体激动剂佐剂的工程化NP治疗导致稳健的抗原特异性CD 8 + T细胞应答，从而在鼠黑素瘤和结肠腺癌的体内模型中产生有效的抗肿瘤治疗。
Dendritic cells (DCs) are a major force in medicine with the ability to induce antigen-specific immune responses. However, transfection of DCs is challenging, and current nanoparticle (NP)-based delivery systems have had limited success in facilitating tissue-mediated delivery to lymphoid organs following systemic administration. We report the design of biodegradable polymeric nanocarriers that enable targeted mRNA delivery to splenic DCs following systemic administration without the need for targeting ligands. We also demonstrate codelivery of adjuvants along with mRNA to trigger costimulatory signaling of DCs to activate antigen-specific CD8+ T cells. The NP design enables robust antitumor immune responses in multiple murine tumor models. This technology is an advancement that validates systemically delivered polymeric mRNA-based cancer vaccines with broad applications. Nanoparticle (NP)-based mRNA cancer vaccines hold great promise to realize personalized cancer treatments. To advance this technology requires delivery formulations for efficient intracellular delivery to antigen-presenting cells. We developed a class of bioreducible lipophilic poly(beta-amino ester) nanocarriers with quadpolymer architecture. The platform is agnostic to the mRNA sequence, with one-step self-assembly allowing for delivery of multiple antigen-encoding mRNAs as well as codelivery of nucleic acid–based adjuvants. We examined structure–function relationships for NP-mediated mRNA delivery to dendritic cells (DCs) and identified that a lipid subunit of the polymer structure was critical. Following intravenous administration, the engineered NP design facilitated targeted delivery to the spleen and preferential transfection of DCs without the need for surface functionalization with targeting ligands. Treatment with engineered NPs codelivering antigen-encoding mRNA and toll-like receptor agonist adjuvants led to robust antigen-specific CD8+ T cell responses, resulting in efficient antitumor therapy in in vivo models of murine melanoma and colon adenocarcinoma.
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DOI：
10.1073/pnas.2005794117
发表时间：
2020-07-28
影响因子：
11.1
作者：
Callmann, Cassandra E.;Cole, Lisa E.;Mirkin, Chad A.
通讯作者：
Mirkin, Chad A.
DOI：
10.1056/nejmoa2035389
发表时间：
2021-02-04
期刊：
The New England journal of medicine
影响因子：
--
作者：
Baden LR;El Sahly HM;Essink B;Kotloff K;Frey S;Novak R;Diemert D;Spector SA;Rouphael N;Creech CB;McGettigan J;Khetan S;Segall N;Solis J;Brosz A;Fierro C;Schwartz H;Neuzil K;Corey L;Gilbert P;Janes H;Follmann D;Marovich M;Mascola J;Polakowski L;Ledgerwood J;Graham BS;Bennett H;Pajon R;Knightly C;Leav B;Deng W;Zhou H;Han S;Ivarsson M;Miller J;Zaks T;COVE Study Group
通讯作者：
COVE Study Group
影响因子：
14
作者：
Islam MA;Rice J;Reesor E;Zope H;Tao W;Lim M;Ding J;Chen Y;Aduluso D;Zetter BR;Farokhzad OC;Shi J
通讯作者：
Shi J
影响因子：
38.3
作者：
Akinc, Akin;Maier, Martin A.;Cullis, Pieter R.
通讯作者：
Cullis, Pieter R.
DOI：
10.1038/s41571-020-00460-2
发表时间：
2021-04
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
Blass E;Ott PA
通讯作者：
Ott PA