A navitoclax-loaded nanodevice targeting matrix metalloproteinase-3 for the selective elimination of senescent cells
Por:
B. ESCRICHE-NAVARRO, E. GARRIDO, F. SANCENÓN, A. GARCÍA-FERNÁNDEZ and R. MARTÍNEZ-MÁÑEZ
Publicada:
1 mar 2024
Ahead of Print:
1 feb 2024
Resumen:
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 beta-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-3dependent 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. (c) 2024 The Author(s). Published by Elsevier Ltd on behalf of Acta Materialia Inc. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )
Filiaciones:
B. ESCRICHE-NAVARRO:
Desarrollo Tecnol IDM Univ Politecn Valencia, Inst Interuniv Invest Reconocimiento Mol & Desarro, Univ Politecn Valencia, Camino Vera S-N, Valencia 46022, Spain
CIBER Bioingn Biomat & Nanomed CIBER BBN, Ave Monforte de Lemos 3-5,Pabellon 11 Planta 0, Madrid 28029, Spain
Un Mixta Invest Nanomed, Unidad Mixta Invest Nanomed & Sensores, IIS La Fe, Ave Fernando Abril Martorell,106 Torre A 7a Planta, Valencia 46026, Spain
E. GARRIDO:
Desarrollo Tecnol IDM Univ Politecn Valencia, Inst Interuniv Invest Reconocimiento Mol & Desarro, Univ Politecn Valencia, Camino Vera S-N, Valencia 46022, Spain
CIBER Bioingn Biomat & Nanomed CIBER BBN, Ave Monforte de Lemos 3-5,Pabellon 11 Planta 0, Madrid 28029, Spain
F. SANCENÓN:
Desarrollo Tecnol IDM Univ Politecn Valencia, Inst Interuniv Invest Reconocimiento Mol & Desarro, Univ Politecn Valencia, Camino Vera S-N, Valencia 46022, Spain
Univ Politecn Valencia, Ctr Invest Principe Felipe, Unidad Mixta UPV CIPF Invest Mecanismos Enfermedad, C Eduardo Primo Yufera 3, Valencia 46012, Spain
CIBER Bioingn Biomat & Nanomed CIBER BBN, Ave Monforte de Lemos 3-5,Pabellon 11 Planta 0, Madrid 28029, Spain
Un Mixta Invest Nanomed, Unidad Mixta Invest Nanomed & Sensores, IIS La Fe, Ave Fernando Abril Martorell,106 Torre A 7a Planta, Valencia 46026, Spain
:
Desarrollo Tecnol IDM Univ Politecn Valencia, Inst Interuniv Invest Reconocimiento Mol & Desarro, Univ Politecn Valencia, Camino Vera S-N, Valencia 46022, Spain
Univ Politecn Valencia, Ctr Invest Principe Felipe, Unidad Mixta UPV CIPF Invest Mecanismos Enfermedad, C Eduardo Primo Yufera 3, Valencia 46012, Spain
CIBER Bioingn Biomat & Nanomed CIBER BBN, Ave Monforte de Lemos 3-5,Pabellon 11 Planta 0, Madrid 28029, Spain
:
Desarrollo Tecnol IDM Univ Politecn Valencia, Inst Interuniv Invest Reconocimiento Mol & Desarro, Univ Politecn Valencia, Camino Vera S-N, Valencia 46022, Spain
Univ Politecn Valencia, Ctr Invest Principe Felipe, Unidad Mixta UPV CIPF Invest Mecanismos Enfermedad, C Eduardo Primo Yufera 3, Valencia 46012, Spain
CIBER Bioingn Biomat & Nanomed CIBER BBN, Ave Monforte de Lemos 3-5,Pabellon 11 Planta 0, Madrid 28029, Spain
Un Mixta Invest Nanomed, Unidad Mixta Invest Nanomed & Sensores, IIS La Fe, Ave Fernando Abril Martorell,106 Torre A 7a Planta, Valencia 46026, Spain
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