Targeted Degradation of Signal Transduction and Activator of Transcription 3 by Chaperone-Mediated Autophagy Targeting Chimeric Nanoplatform.
ACS Nano
; 18(2): 1599-1610, 2024 Jan 16.
Article
in En
| MEDLINE
| ID: mdl-38157218
ABSTRACT
Chaperone-mediated autophagy (CMA) is a lysosomal-dependent proteolysis pathway for the degradation of cytosolic proteins. However, exploiting CMA-mediated proteolysis to degrade proteins of interest in cancer therapy has not been widely applied. In this study, we develop a CMA-targeting chimera (CMATAC) to efficiently and specifically degrade signal transduction and activator of transcription 3 (STAT3) in tumor cells. CMATAC consists of STAT3 and heat shock cognate 70 kDa protein (HSC70) targeting peptides connected by a linker. To efficiently deliver CMATACs into tumor cells, lipid nanoparticles (LNPs) are used to encapsulate CMATACs (nCMATACs) and decorated with an insulin-like growth factor 2 receptor (IGF2R) targeting peptide (InCMATACs) to achieve tumor targeting and precise delivery. The CMA pathway is activated in tumor cells by a fasting-mimicking diet (FMD). Furthermore, FMD treatment strongly enhances the cellular uptake and tumor accumulation of InCMATACs by upregulating the IGF2R expression. As a result, InCMATACs efficiently degrade STAT3 protein in both A549 and HCC827 tumor cells and inhibit tumor growths in vivo. This study demonstrates that InCMATACs can be used for selective proteolysis in cancer therapy.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Chaperone-Mediated Autophagy
/
Neoplasms
Limits:
Humans
Language:
En
Journal:
ACS Nano
Year:
2024
Document type:
Article
Affiliation country:
China
Country of publication:
Estados Unidos