Issue 1, 2025

A dual-locked cyclopeptide–siRNA conjugate for tumor-specific gene silencing

Abstract

Strategies allowing tumor-selective siRNA delivery while minimizing off-tumor gene silencing effects are highly demanded to advance cancer gene therapy, which however still remain challenging. We herein report a dual-locking bioconjugation approach to address this challenge. A dual-locked cyclopeptide–siRNA conjugate (DPRC) was designed to simultaneously endow siRNA with tumor-targeting properties and tumor-biomarker/visible-light dually controllable action. The DPRC consisted of a programmed death-ligand 1 (PD-L1)-targeting cyclopeptide as a tumor-homing ligand and B-cell lymphoma-2 (Bcl-2)-targeting siRNA as a payload. They were conjugated via a tandem-responsive cleavable linker containing a photocleavable coumarin moiety quenched by naphthylamide through a disulfide linkage. Owing to the interaction between cell-membrane PD-L1 and the cyclopeptide, the DPRC was efficiently taken up by PD-L1-positive cancer cells. Notably, the internalized DPRC could only release and restore the gene silencing activity of siBcl-2 upon GSH-mediated disulfide bond breakage followed by visible light irradiation on the coumarin moiety to induce photo-cleavage. The released siBcl-2 further silenced the expression of anti-apoptotic Bcl-2 to suppress cancer cell growth. We demonstrated the tumor-targeting and dual-locked action of siRNA by the DPRC in both two-dimensional and three-dimensional cancer cell cultures. This study thus presents a novel strategy for precise tumor-specific gene silencing by siRNA.

Graphical abstract: A dual-locked cyclopeptide–siRNA conjugate for tumor-specific gene silencing

Supplementary files

Article information

Article type
Paper
Submitted
10 Oct 2024
Accepted
23 Nov 2024
First published
25 Nov 2024
This article is Open Access
Creative Commons BY-NC license

RSC Chem. Biol., 2025,6, 73-80

A dual-locked cyclopeptide–siRNA conjugate for tumor-specific gene silencing

C. Li, S. Sun, H. Kong, X. Xie, G. Liang, Y. Zhang, H. Wang and J. Li, RSC Chem. Biol., 2025, 6, 73 DOI: 10.1039/D4CB00247D

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