Senolytic Therapy Enabled by Senescent Cell-Sensitive Biomimetic Melanin Nano-senolytics.

Abstract

Cellular senescence is a significant risk factor for aging and age-related diseases (ARD). The canonical senolytics Dasatinib and Quercetin (DQ) have shown promise in clearing senescent cells (SnCs); however, the lack of selectivity poses a challenge in achieving optimal outcomes. Despite the recent occurrence of the nanomaterial-based approaches targeting SnCs, limited therapeutic effects and potential toxicity still remain a major concern. Herein, we developed a "double locks-like" nanoplatform that integrated Galactan coating and mesoporous polydopamine to encase the senolytic drug DQ. By this way, DQ was only released in SnCs that were featured with higher levels of β-galactosidase (β-gal) and low PH. Additionally, the nanoparticles were equipped with 2,2,6,6-Tetramethylpiperidine-1-oxyl (Tempo) to gain enhanced photothermal converting potential. Consequently, the synthesized nanosenolytics demonstrated remarkable specificity and efficacy in eradicating SnCs, and accordingly reversed pulmonary fibrosis in mice without affecting normal tissues. Upon exposure of near-infrared (NIR) light, the nanoparticles demonstrated to efficiently remove senescent tumor cells inducted by chemotherapy, thereby hindering the outgrowth and metastasis or breast cancer. Collectively, the present study develops an "On/Off" switchable nanoplatform in response to SnCs, and produces a more safe, efficient and feasible way to delay aging or alleviate age-associated diseases. This article is protected by copyright. All rights reserved.