POS8-1256
Targeting ER Unfolded Proteins via Enzyme-Activated Disulfide Oligomerization for Selective Cancer Therapy
Topic
S8. Frontiers of Functional Polymers in Biology and Medicine
When and Where
Sep 30, 2026
08:30 - 09:30
Room 301 (Grand Ballroom)
Session Chairs
Heesuk KIM
Jinhye BAE
Presenter(s)
Min-Seok Seu (Ulsan National Institute of Science & Technology (UNIST))
Co-Author(s)
Abstract
Targeting endoplasmic reticulum (ER) proteostasis represents a powerful approach for cancer therapy, as malignant cells exhibit heightened dependency on ER-resident folding machinery to handle unfolded proteins. In this study, we leverage this vulnerability using an ER-localized, enzyme-responsive disulfide oligomerization platform. Our design centers on TsNA@DTE, a thioester-shielded precursor that is selectively cleaved by upregulated thioesterases within the ER. Upon activation, the liberated dithiols assemble into disulfide oligomers under the ER’s oxidizing conditions. These oligomers then capture unfolded proteins through thiol-disulfide exchange, leading to severe protein aggregation and acute ER stress. Cell-free evaluations validated this mechanism, showing that the active species selectively cross-linked reduced bovine serum albumin (BSA) and driven its aggregation, while non-reactive or monovalent controls remained inert. In vitro, TsNA@DTE preferentially partitioned into the ER, conjugated with the unfolded protein pool, and triggered robust UPR-mediated apoptotic signaling. Notably, the precursor showed potent cytotoxicity toward HeLa cancer cells with minimal impact on NIH3T3 normal cells. These results highlight enzyme-triggered, ER-targeted disulfide assembly as a promising and highly selective strategy for cancer-targeted therapy.
