Nanodevice-Mediated Immune Cell Recruitment: Targeting Senescent Cells via MMP-3-Responsive CXCL12-Coated Nanoparticles

Abstract

Senescent cells are involved in age-related disorders in different organs and are therapeutic targets for fibrotic and chronic pathologies. Immune-modulating agents, able to enhance senescent cell detection and elimination by endogenous immune cells, have emerged as pharmacological strategies. We report herein a nanoparticle for immune cell-mediated senolytic therapy designed to recruit immune cells in response to specific enzymatic matrix metalloproteinase-3 (MMP-3) activity in the senescence-associated secretory phenotype. For this, mesoporous silica nanoparticles (MSNs) are coated with a peptide substrate of the metalloproteinase MMP-3, and the peptide is decorated with chemokine CXCL12 that enhances immune cell recruitment (NPs@CXCL12). Controlled release studies confirmed the progressive and specific release of CXCL12 in the presence of MMP-3. The ability of immune cell recruitment in response to a senescent microenvironment (senescent WI-38 fibroblasts) is confirmed by Transwell migration assays with green fluorescent Jurkat T-cells, showing NPs@CXCL12 has an enhanced chemotaxis effect toward senescent cells compared to free CXCL12 (2-fold). Moreover, the cytotoxic capacity of human primary natural killer (NK) cells over senescent WI-38 is also confirmed, and their migration trajectories in response to NPs@CXCL12 or free CXCL12 are monitored by using a microfluidic device. Results confirm the ability of NPs@CXCL12 to generate a chemotactic gradient able to attract NK cells. When compared with free CXCL12, the NPs@CXCL12 system showed a reduction of up to 15.56% in the population of NK cells migrating toward free CXCL12 under competitive conditions. This study demonstrates the potential of designing nanoparticles to recruit immune cells under specific responses to eliminate senescent cells. Results confirm that NPs@CXCL12 can effectively establish a chemotactic gradient to attract NK cells.