Biodegradable lipophilic polymeric mRNA nanoparticles for ligand-free targeting of splenic dendritic cells for cancer vaccination

被引：48

作者：

Ben-Akiva, Elana ^{[1
,2
,3
,4
]}

Karlsson, Johan ^{[1
,2
,3
,5
]}

Hemmati, Shayan ^{[1
,2
,3
]}

Yu, Hongzhe ^{[1
,2
,3
]}

Tzeng, Stephany Y. ^{[1
,2
,3
]}

Pardoll, Drew M. ^{[4
,6
,7
,8
,9
]}

Green, Jordan J. ^{[1
,2
,3
,4
,6
,10
,11
,12
,13
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Baltimore, MD 21231 USA

[2] Johns Hopkins Univ, Sch Med, Translat Tissue Engn Ctr, Baltimore, MD 21231 USA

[3] Johns Hopkins Univ, Sch Med, Inst NanoBioTechnol, Baltimore, MD 21231 USA

[4] Sidney Kimmel Comprehens Canc Ctr, Bloomberg Kimmel Inst Canc Immunotherapy, Baltimore, MD 21287 USA

[5] Uppsala Univ, Dept Chem, Angstrom Lab, SE-75121 Uppsala, Sweden

[6] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21231 USA

[7] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21231 USA

[8] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21231 USA

[9] Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21231 USA

[10] Johns Hopkins Univ, Dept Mat Sci & Engn, Baltimore, MD 21231 USA

[11] Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD 21231 USA

[12] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21231 USA

[13] Johns Hopkins Univ, Sch Med, Dept Neurosurg, Baltimore, MD 21231 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2023年 / 120卷 / 26期

基金：

瑞典研究理事会;

关键词：

mRNA; nanoparticle; delivery; cancer; vaccine; IN-VIVO; DELIVERY; TRANSLATION; VACCINES; INNATE;

D O I：

10.1073/pnas.2301606120

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Nanoparticle (NP) -based mRNA cancer vaccines hold great promise to realize person-alized 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 architec-ture. The platform is agnostic to the mRNA sequence, with one -step self-assembly allow-ing 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 pol-ymer 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.

引用

页数：12

共 21 条

[21] A NRAS mRNA G-quadruplex structure-targeting small-molecule ligand reactivating DNA damage response in human cancer cells for combination therapy with clinical PI3K inhibitors
Chan, Ka-Hin
Zheng, Bo-Xin
Leung, Alan Siu-Lun
Long, Wei
Zhao, Yuchen
Zheng, Yingying
Wong, Wing-Leung
[J]. INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES, 2024, 279

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