Abstract
Myocardial infarction (MI) results in oxidative stress to the myocardium and frequently leads to heart failure (HF). There is an unmet clinical need to develop therapeutics that address the inflammatory stress response and prevent negative left ventricular remodeling. Here, the Keap1/Nrf2 protein–protein interaction is specifically targeted, as Nrf2 activation is known to mitigate the inflammatory response following MI. This is achieved using a Nrf2-mimetic protein-like polymer (PLP) to inhibit the Keap1-Nrf2 interaction. The PLP platform technology provides stability in vivo, potent intracellular bioactivity, and multivalency leading to high avidity Keap1 binding. In vitro and in vivo assays to probe cellular activity and MI therapeutic utility are employed. These Keap1-inhibiting PLPs (Keap1i-PLPs) impart cytoprotection from oxidative stress via Nrf2 activation at sub-nanomolar concentrations in primary cardiomyocytes. Single-digit mg kg−1, single-dose, intravenous PLP administration significantly improves cardiac function in rats post-MI through immunomodulatory, anti-apoptotic, and angiogenic mechanisms. Thus Keap1i-PLPs disrupt key intracellular protein–protein interactions following intravenous, systemic administration in vivo. These results have broad implications not only for MI but also for other oxidative stress-driven diseases and conditions.
| Original language | English (US) |
|---|---|
| Journal | Advanced Materials |
| DOIs | |
| State | Accepted/In press - 2025 |
Funding
This work was made possible by a research grant from the National Institutes of Health National Heart, Lung, and Blood Institute (NHLBI) grant (2R01HL139001, R00 CA248715). J.M.M. was supported by an American Heart Association (AHA) pre\u2010doctoral fellowship (23PRE1023221) and an NHLBI Training Grant T32HL105373. K.P.C. was supported via an NIH pre\u2010doctoral fellowship (1F30AG076317\u201001A1). A.C. was supported by an AHA pre\u2010doctoral fellowship (24PRE1180449) and an NIH, NIBIB Training Grant T32EB009380. M.B.N. was supported by an AHA post\u2010doctoral fellowship (24POST1242447) and an NIH T32 Training Grant T32HL007444. J.D.H. was supported by an NIH NHLBI predoctoral fellowship (F31HL158212) and an NIH NHLBI Training Grant T32HL105373. X.Z. was supported by Damon Runyon Cancer Research Foundation funds (DFS\u201053\u201022). The authors of this paper would like to thank Dr. Elsa Molina and Christian Quintero at the Salk Institute for Biological Studies for running the NanoString nCounter platform for RNA samples, and Charles Zamilpa from the Imaging Core at the Sanford Consortium for Regenerative Medicine for acquiring cardiac MRI images. The authors would also like to thank Dr. Michael Davis and his lab for providing rat cardiac endothelial cells, and Dr. Kevin King, Dr. Zhenxing Fu, and Justin Yu for providing murine bone marrow\u2010derived macrophages. Further, the authors would like to thank Yang Li and Baofu Qiao for in silico modeling, the Keck Biophysics Facility, a shared resource of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University supported in part by the NCI Cancer Center Support Grant #P30 CA060553 was used in this work in addition to Northwestern's High Throughput Analysis Core (support from the Lurie Cancer Center (P30CA060553)). Monomer characterization was performed at the IMSERC MS facility at Northwestern University, which has received support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS\u20102025633).
Keywords
- biomaterial
- drug delivery
- myocardial infarction
- polymers
ASJC Scopus subject areas
- General Materials Science
- Mechanics of Materials
- Mechanical Engineering
