PMID- 38185231 OWN - NLM STAT- MEDLINE DCOM- 20240219 LR - 20240219 IS - 1878-7568 (Electronic) IS - 1742-7061 (Linking) VI - 176 DP - 2024 Mar 1 TI - A navitoclax-loaded nanodevice targeting matrix metalloproteinase-3 for the selective elimination of senescent cells. PG - 405-416 LID - S1742-7061(24)00002-3 [pii] LID - 10.1016/j.actbio.2024.01.002 [doi] AB - 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-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. CI - Copyright (c) 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved. FAU - Escriche-Navarro, Blanca AU - Escriche-Navarro B AD - Instituto Interuniversitario de Investigacion de Reconocimiento Molecular y Desarrollo Tecnologico (IDM) Universitat Politecnica de Valencia, Universitat de Valencia, Camino de Vera, s/n. 46022, Valencia, Spain; CIBER de Bioingenieria, Biomateriales y Nanomedicina (CIBER-BBN), Av. Monforte de Lemos, 3-5. Pabellon 11. Planta 0, 28029 Madrid, Spain; Unidad Mixta de Investigacion en Nanomedicina y Sensores, Universitat Politecnica de Valencia, IIS La Fe. Av. Fernando Abril Martorell, 106 Torre A 7 feminine planta, 46026, Valencia, Spain. FAU - Garrido, Eva AU - Garrido E AD - Instituto Interuniversitario de Investigacion de Reconocimiento Molecular y Desarrollo Tecnologico (IDM) Universitat Politecnica de Valencia, Universitat de Valencia, Camino de Vera, s/n. 46022, Valencia, Spain; CIBER de Bioingenieria, Biomateriales y Nanomedicina (CIBER-BBN), Av. Monforte de Lemos, 3-5. Pabellon 11. Planta 0, 28029 Madrid, Spain. FAU - Sancenon, Felix AU - Sancenon F AD - Instituto Interuniversitario de Investigacion de Reconocimiento Molecular y Desarrollo Tecnologico (IDM) Universitat Politecnica de Valencia, Universitat de Valencia, Camino de Vera, s/n. 46022, Valencia, Spain; Unidad Mixta UPV-CIPF de Investigacion en Mecanismos de Enfermedades y Nanomedicina, Universitat Politecnica de Valencia, Centro de Investigacion Principe Felipe, C/ Eduardo Primo Yufera 3, 46012, Valencia, Spain; CIBER de Bioingenieria, Biomateriales y Nanomedicina (CIBER-BBN), Av. Monforte de Lemos, 3-5. Pabellon 11. Planta 0, 28029 Madrid, Spain; Unidad Mixta de Investigacion en Nanomedicina y Sensores, Universitat Politecnica de Valencia, IIS La Fe. Av. Fernando Abril Martorell, 106 Torre A 7 feminine planta, 46026, Valencia, Spain. FAU - Garcia-Fernandez, Alba AU - Garcia-Fernandez A AD - Instituto Interuniversitario de Investigacion de Reconocimiento Molecular y Desarrollo Tecnologico (IDM) Universitat Politecnica de Valencia, Universitat de Valencia, Camino de Vera, s/n. 46022, Valencia, Spain; Unidad Mixta UPV-CIPF de Investigacion en Mecanismos de Enfermedades y Nanomedicina, Universitat Politecnica de Valencia, Centro de Investigacion Principe Felipe, C/ Eduardo Primo Yufera 3, 46012, Valencia, Spain; CIBER de Bioingenieria, Biomateriales y Nanomedicina (CIBER-BBN), Av. Monforte de Lemos, 3-5. Pabellon 11. Planta 0, 28029 Madrid, Spain. Electronic address: algarfe4@etsia.upv.es. FAU - Martinez-Manez, Ramon AU - Martinez-Manez R AD - Instituto Interuniversitario de Investigacion de Reconocimiento Molecular y Desarrollo Tecnologico (IDM) Universitat Politecnica de Valencia, Universitat de Valencia, Camino de Vera, s/n. 46022, Valencia, Spain; Unidad Mixta UPV-CIPF de Investigacion en Mecanismos de Enfermedades y Nanomedicina, Universitat Politecnica de Valencia, Centro de Investigacion Principe Felipe, C/ Eduardo Primo Yufera 3, 46012, Valencia, Spain; CIBER de Bioingenieria, Biomateriales y Nanomedicina (CIBER-BBN), Av. Monforte de Lemos, 3-5. Pabellon 11. Planta 0, 28029 Madrid, Spain; Unidad Mixta de Investigacion en Nanomedicina y Sensores, Universitat Politecnica de Valencia, IIS La Fe. Av. Fernando Abril Martorell, 106 Torre A 7 feminine planta, 46026, Valencia, Spain. Electronic address: rmaez@qim.upv.es. LA - eng PT - Journal Article DEP - 20240105 PL - England TA - Acta Biomater JT - Acta biomaterialia JID - 101233144 RN - XKJ5VVK2WD (navitoclax) RN - EC 3.4.24.17 (Matrix Metalloproteinase 3) RN - 0 (Senotherapeutics) RN - 0 (Aniline Compounds) RN - 0 (Biomarkers) RN - 0 (Sulfonamides) SB - IM MH - *Matrix Metalloproteinase 3 MH - *Senotherapeutics MH - Cellular Senescence MH - Aniline Compounds/pharmacology MH - Biomarkers MH - *Sulfonamides OTO - NOTNLM OT - Matrix metalloproteinase-3 OT - Mesoporous silica nanoparticles OT - Navitoclax OT - Senescence COIS- Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2024/01/08 00:42 MHDA- 2024/02/19 06:44 CRDT- 2024/01/07 19:15 PHST- 2023/10/10 00:00 [received] PHST- 2023/12/18 00:00 [revised] PHST- 2024/01/01 00:00 [accepted] PHST- 2024/02/19 06:44 [medline] PHST- 2024/01/08 00:42 [pubmed] PHST- 2024/01/07 19:15 [entrez] AID - S1742-7061(24)00002-3 [pii] AID - 10.1016/j.actbio.2024.01.002 [doi] PST - ppublish SO - Acta Biomater. 2024 Mar 1;176:405-416. doi: 10.1016/j.actbio.2024.01.002. Epub 2024 Jan 5.