Biomaterials ResearchOct 3, 2025

A Self-Assembling Drug with Better Absorption That Selectively Targets Aging Cells in the Eye's Light-Filtering Tissue

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Jan 7, 2026

Abstract

N201-gal, a novel senolytic prodrug, significantly restored retinal tissue integrity and visual function in mice with doxorubicin-induced retinal senescence.

N201-gal is designed to selectively eliminate senescent cells while sparing normal cells.
This prodrug self-assembles into nanoparticles that enable oral administration and improve systemic bioavailability.
Once inside senescent cells, N201-gal is activated by β-galactosidase, leading to controlled drug release.
In vitro studies show that N201-gal reduces markers associated with cellular aging in retinal pigment epithelial cells.
The nanoparticle formulation displays favorable properties for gastrointestinal absorption, including uniform particle size and pH stability.

Simplified

Senolytic therapy, which targets and selectively eliminates senescent cells, has emerged as a promising strategy for treating various age-related diseases. However, its clinical application is often limited by poor bioavailability, off-target toxicity, and the need for invasive administration routes. To overcome these challenges, we developed N201-gal, a novel β-galactosidase-reactive senolytic prodrug that self-assembles into stable nanoparticles, enabling oral administration and improved systemic bioavailability. Once internalized by senescent cells, N201-gal responds to β-galactosidase overexpression, triggering controlled drug release and inducing selective apoptosis in senescent cells while sparing normal cells. The nanoparticle formulation exhibited favorable physicochemical properties, including uniform particle size and pH stability suitable for gastrointestinal absorption. In vitro study shows that N201-gal demonstrated potent senolytic activity and reduced the expression of senescence-associated markers in retinal pigment epithelial (RPE) cells. In addition, in vivo study also shows that oral administration of N201-gal in a mouse model of doxorubicin-induced retinal senescence model significantly restored retinal tissue integrity and visual function through the targeted clearance of senescent cells. These findings highlight the potential of self-assembling senolytic prodrugs as a noninvasive and targeted therapeutic platform for age-related degenerative diseases.

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Funding

Competing interests

Competing interests: H.O., C.K., and J.-H.R. are inventors on a patent application related to this work (Korean patent 10-2023-0141604 and PCT/KR2023/004208). All other authors declare no competing interests.

PubMed

A Self-Assembling Drug with Better Absorption That Selectively Targets Aging Cells in the Eye's Light-Filtering Tissue

Abstract

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Competing interests

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Abstract

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Funding

Competing interests

Related papers

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