A navitoclax-loaded nanodevice targeting matrix metalloproteinase-3 for the selective elimination of senescent cells.

Acta Biomater

Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM) Universitat Politècnica de València, Universitat de València, Camino de Vera, s/n. 46022, Valencia, Spain; Unidad Mixta UPV-CIPF de Investigación en Mecanismos de Enfermedades y Nanomedicina, Universitat Politècnica de València, Centro de Investigación Príncipe Felipe, C/ Eduardo Primo Yúfera 3, 46012, Valencia, Spain; CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Av. Monforte de Lemos, 3-5. Pabellón 11. Planta 0, 28029 Madrid, Spain; Unidad Mixta de Investigación en Nanomedicina y Sensores, Universitat Politècnica de València, IIS La Fe. Av. Fernando Abril Martorell, 106 Torre A 7ª planta, 46026, Valencia, Spain. Electronic address:

Published: March 2024

AI Article Synopsis

  • Cellular senescence contributes to age-related disorders, and selectively eliminating these senescent cells (senolysis) is a promising therapy, though a universal biomarker for their identification remains challenging.
  • Researchers developed a novel nanodevice utilizing mesoporous silica nanoparticles coated with a peptide that targets matrix metalloproteinase-3 (MMP-3), an enzyme prevalent in senescent cells, to enhance selective senolytic therapy.
  • The study showed that this targeted delivery system selectively decreased the viability of senescent cells while protecting healthy non-proliferating cells, indicating potential clinical applications for improved senolytic treatments.

Article Abstract

Cellular senescence is implicated in the occurrence and progression of multiple age-related disorders. In this context, the selective elimination of senescent cells, senolysis, has emerged as an effective therapeutic strategy. However, the heterogeneous senescent phenotype hinders the discovery of a universal and robust senescence biomarker that limits the effective of senolytic with off-target toxic effects. Therefore, the development of more selective strategies represents a promising approach to increase the specificity of senolytic therapy. In this study, we have developed an innovative nanodevice for the selective elimination of senescent cells (SCs) based on the specific enzymatic activity of the senescent secretome. The results revealed that when senescence is induced in proliferating WI-38 by ionizing radiation (IR), the cells secrete high levels of matrix metalloproteinase-3 (MMP-3). Based on this result, mesoporous silica nanoparticles (MSNs) were loaded with the senolytic navitoclax (Nav) and coated with a specific peptide which is substrate of MMP-3 (NPs(Nav)@MMP-3). Studies in cells confirmed the preferential release of cargo in IR-induced senescent cells compared to proliferating cells, depending on MMP-3 levels. Moreover, treatment with NPs(Nav)@MMP-3 induced a selective decrease in the viability of SCs as well as a protective effect on non-proliferating cells. These results demonstrate the potential use of NPs to develop enhanced senolytic therapies based on specific enzymatic activity in the senescent microenvironment, with potential clinical relevance. STATEMENT OF SIGNIFICANCE: The common β-galactosidase activity has been exploited to develop nanoparticles for the selective elimination of senescent cells. However, the identification of new senescent biomarkers is a key factor for the development of improved strategies. In this scenario, we report for the first time the development of NPs targeting senescent cells based on specific enzymatic activity of the senescent secretome. We report a navitoclax-loaded nanodevice responsive to the matrix metalloproteinase-3 (MMP-3) associated with the senescent phenotype. Our nanosystem achieves the selective release of navitoclax in an MMP-3-dependent manner while limiting off-target effects on non-senescent cells. This opens the possibility of using nanoparticles able to detect an altered senescent environment and selectively release its content, thus enhancing the efficacy of senolytic therapies.

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Source
http://dx.doi.org/10.1016/j.actbio.2024.01.002DOI Listing

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