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Published on: May 10, 2022
Multiscale molecular modeling-directed ROS-responsive nanotherapy for dual-axis regulation of fibrotic and
Hong Sang Choi1, Aravindkumar Sundaram2,3, Arathy Vasukutty2
1Department of Internal Medicine, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea.
Background:
In Alport nephropathy, tightly interconnected fibrotic, inflammatory, and oxidative cascades are activated, elevating reactive oxygen species (ROS) that intensify renal injury. The broad activation of stress-responsive and profibrotic pathways further induces disease progression and limits the efficacy of monotherapies.
Results:
We performed structure-based docking and long-timescale molecular dynamics simulations to identify mechanistically complementary agents, enabling the assessment of ligand stability, specificity, and suitability for selecting an effective drug combination. These analyses revealed stable histone deacetylase binding by ivaltinostat and sustained JNK1 engagement by genistein, supporting their selection as complementary antifibrotic and anti-inflammatory agents. To translate these insights, we engineered PEG-TK-C18/DSPE-PEG-maleimide nanomixed micelles that are functionalized with the proximal-tubule-targeting peptide (KKEEE)₃K-C (PPCK), co-loading both drugs, to yield PPCK + IG. Thioketal linkages conferred ROS-responsive cleavage and controlled release, while (KKEEE)₃K-C enhanced proximal tubule targeting. In Col4a3-/- mice, PPCK + IG exhibited selective renal accumulation, oxidative activation, and robust suppression of fibrotic (α-SMA, fibronectin, and p-Smad2/3) and inflammatory markers (p-JNK, IL-6, and MCP-1), as well as downstream ERK attenuation, significantly improving renal function.
Conclusions:
The findings of our study demonstrate precision nanotherapy that exploits pathological oxidative stress for targeted delivery and the coordinated modulation of epigenetic and MAPK pathways, offering a promising strategy for Alport nephropathy and other chronic kidney diseases.
Insights
This study developed a novel nanotherapy for Alport nephropathy, combining drugs to target kidney fibrosis and inflammation. The therapy effectively delivered treatments to the kidneys, improving renal function in mice.
Area of Science:
- Nephrology
- Nanomedicine
- Pharmacology
Background:
- Alport nephropathy involves complex fibrotic, inflammatory, and oxidative stress pathways that worsen kidney injury.
- Existing single-drug treatments are limited by broad pathway activation and disease progression.
Purpose of the Study:
- To identify and combine complementary therapeutic agents for Alport nephropathy.
- To engineer a targeted nanodelivery system for enhanced drug efficacy and reduced side effects.
Main Methods:
- Structure-based docking and molecular dynamics simulations identified ivaltinostat and genistein as complementary agents.
- A ROS-responsive nanomicelle system (PPCK+IG) was engineered, co-loading both drugs and functionalized with a kidney-targeting peptide.
- In vivo efficacy was assessed in Col4a3-/- mice.
Main Results:
- The nanomicelles selectively accumulated in the kidneys and released drugs in response to oxidative stress.
- PPCK+IG significantly suppressed fibrotic markers (α-SMA, fibronectin, p-Smad2/3) and inflammatory markers (p-JNK, IL-6, MCP-1).
- Downstream ERK signaling was attenuated, leading to significant improvement in renal function.
Conclusions:
- Precision nanotherapy effectively targets pathological oxidative stress for drug delivery in Alport nephropathy.
- Coordinated modulation of epigenetic and MAPK pathways offers a promising therapeutic strategy.
- This approach holds potential for treating Alport nephropathy and other chronic kidney diseases.
