Targeted delivery of immune-stimulating bispecific RNA, inducing apoptosis and anti-tumor immunity in cancer cells.

Fiche publication

Date publication

mars 2024

Journal

iScience

Auteurs

Membres identifiés du Cancéropôle Est :
Dr CIANFERANI Sarah , Dr WAGNER Alain , Dr CHAUBET Guilhem

Tous les auteurs :
Rady T, Erb S, Deddouche-Grass S, Morales R, Chaubet G, Cianférani S, Basse N, Wagner A

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/38380254

Résumé

Double-stranded RNAs (dsRNA)-based strategies appeared as promising therapies to induce an inflammation in the tumor microenvironment. However, currently described systems generally lack active targeting of tissues, and their clinical translation is thus limited to intratumoral injection. Herein, we developed an antibody-siRNA-5'triphosphate conjugate with multiple modes of action, combining cell surface EphA2-specific internalization, leading to a simultaneous gene silencing and activation of the receptor retinoic acid-inducible gene I (RIG-I). Recognition of cytosolic siRNA-5'triphosphate by RIG-I triggers the expression of interferons and pro-inflammatory cytokines, inducing an inflammation of the tumor environment and activating neighboring immune cells. In addition, these RIG-I-specific effects synergized with siRNA-mediated PLK1 silencing to promote cancer cell death by apoptosis. Altogether, such immune-stimulating antibody-RNA conjugate opens a novel modality to overcome some limitations encountered by dsRNA molecules currently in clinical trials.