Targeted Degradation of STAT3 via Chaperone-Mediated Autophagy by nanoCMATAC Platform

Abstract

Chaperone mediated autophagy (CMA) is a lysosomal-dependent proteolysis pathway for degradation of cytosolic proteins. However, degradation of "undruggable" proteins for cancer therapy has not yet achieved by utilizing CMA-mediated proteolysis. We develop a CMA-targeting chimera (CMATAC) for potently and specifically degrading "undruggable" STAT3 in tumor cells. The CMATAC is composed of STAT3 and HSC70 targeting peptides and connected with a linker. To deliver CMATACs in tumor cells, lipid nanoparticles are used to encapsulate CMATACs (nCAMTACs) and decorated with IGF2R targeting peptide (InCAMTACs) for precise delivery. The CMA pathway is activated in tumor cells by treating with fasting-mimicking diet (FMD). In addition, FMD treatment strongly enhances the cellular uptake and tumor accumulation of InCAMTACs by upregulating IGF2R expression. InCAMTACs efficiently degrade the STAT3 proteins in both A549 and HCC827 tumor cells and inhibit the tumor growths in vivo. This study confirms InCAMTACs can be used for selective proteolysis in cancer therapy.

Funding Information: This work was financially supported by NSFC (31971307) and the Start-up Foundation of NCNST, CAS.

Declaration of Interests: The authors declare no competing financial interests.

Ethics Approval Statement: All animal experiments were performed in accordance with relevant national laws and regulations and followed institutional guidelines approved by the Institutional Animal Care and Use Committee of the National Center for Nanotechnology.

Keywords: Chaperone-mediated autophagy, protein degradation, lipid nanoparticles, targeted delivery