Investigation of the enhanced antitumour potency of STING agonist after conjugation to polymer nanoparticles

被引：88

作者：

Dosta, Pere ^{[1
,2
,3
]}

Cryer, Alexander M. ^{[1
,2
,3
]}

Dion, Michelle Z. ^{[1
,2
,3
,4
]}

Shiraishi, Tsubasa ^{[5
]}

Langston, Steven P. ^{[5
]}

Lok, David ^{[5
]}

Wang, Jianing ^{[5
]}

Harrison, Sean ^{[5
]}

Hatten, Tiquella ^{[5
]}

Ganno, Michelle L. ^{[5
]}

Appleman, Vicky A. ^{[5
]}

Taboada, Gonzalo Munoz ^{[6
]}

Puigmal, Nuria ^{[1
,2
,3
]}

Ferber, Shiran ^{[1
,2
]}

Kalash, Santhosh ^{[1
,2
]}

Prado, Michaela ^{[1
,2
]}

Rodriguez, Alma L. ^{[1
,2
]}

Kamoun, Walid S. ^{[5
]}

Abu-Yousif, Adnan O. ^{[5
]}

Artzi, Natalie ^{[1
,2
,3
]}

机构：

[1] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA

[2] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Div Engn Med, Boston, MA 02115 USA

[3] Harvard Univ, Wyss Inst Biolog Inspired Engn, Boston, MA 02115 USA

[4] MIT, Harvard MIT Div Hlth Sci & Technol, Cambridge, MA USA

[5] Takeda Dev Ctr Amer Inc TDCA, Lexington, MA USA

[6] Biodevek, Cambridge, MA USA

来源：

NATURE NANOTECHNOLOGY | 2023年 / 18卷 / 11期

关键词：

CYCLIC GMP-AMP; POLY(BETA-AMINO ESTER)S; CGAS; DELIVERY; 2ND-MESSENGER; EXPRESSION; PATHWAY; CELLS;

D O I：

10.1038/s41565-023-01447-7

中图分类号：

TB3 [工程材料学];

学科分类号：

0805 ; 080502 ;

摘要：

Intravenously administered cyclic dinucleotides and other STING agonists are hampered by low cellular uptake and poor circulatory half-life. Here we report the covalent conjugation of cyclic dinucleotides to poly(& beta;-amino ester) nanoparticles through a cathepsin-sensitive linker. This is shown to increase stability and loading, thereby expanding the therapeutic window in multiple syngeneic tumour models, enabling the study of how the long-term fate of the nanoparticles affects the immune response. In a melanoma mouse model, primary tumour clearance depends on the STING signalling by host cells-rather than cancer cells-and immune memory depends on the spleen. The cancer cells act as a depot for the nanoparticles, releasing them over time to activate nearby immune cells to control tumour growth. Collectively, this work highlights the importance of nanoparticle structure and nano-biointeractions in controlling immunotherapy efficacy. STING agonists are often limited by low circulation time and cellular uptake. The conjugation of STING agonists with polymer nanoparticles is shown to enhance stability, circulation time and cellular uptake, increasing the immunotherapeutic activity.

引用

页码：1351 / +

页数：21

共 59 条

[1] cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING [J].