Work

Endoplasmic reticulum stress induced autophagy alters cellular processing of cationic lipid delivered siRNAs

Year: 2026

Type: article

Abstract: siRNA therapeutics have achieved increased clinical success in the past decade. To achieve a therapeutic effect, siRNAs must enter the cytoplasm of the target cells. Thus, their function typically relies on proper endocytosis and trafficking. Endoplasmic reticulum (ER) stress is associated with diseases that are being studied for treatment with siRNAs (cancer, amyloids, mutations, etc.) and common comorbidities (obesity, smoking, hypertension, etc.). ER stress results in activation of the Unfolded Protein Response (UPR), which initiates changes in cellular function that include disruption to endosomal vesicle trafficking and processing. We used the N-glycosylation inhibitor, tunicamycin, to induce ER stress in HeLa cells during transfection with siRNAs targeting EGFP. Our results showed that ER stress resulted in an increased accumulation of siRNA but a reduction in silencing of the siRNA target (EGFP). Further, we used 3-methyladenine (autophagy inhibitor) and bafilomycin A1 (inhibits endosome maturation) to show that autophagy plays a role in increasing siRNA accumulation. Finally, we showed that the additional accumulated siRNA in ER-stressed cells remained functional, was retained in cells for longer, and prolonged silencing. Our results will inform the design of siRNA delivery vehicles and dosing schedules, by ensuring that disease complications, specifically ER stress/UPR activation, are considered.

Source: Drug Delivery and Translational Research

DOI: 10.1007/s13346-026-02096-8

Authors: R. Chauncey Splichal, Christina Chan, S. Patrick Walton

Institution: Michigan State University

Language: English

Topic: RNA Interference and Gene Delivery

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $4,690