On-Demand Collaborative Delivery for Remodeling the Senescent Microenvironment in Intervertebral Disc Degeneration

The senescent microenvironment, defined as the cellular environment surrounding senescent cells, plays a pivotal role in tissue degenerative diseases by promoting inflammation, disrupting extracellular matrix homeostasis, and inducing senescence in neighboring healthy cells. By analyzing the etiology of the senescent microenvironment in intervertebral disc degeneration (IVDD), senescence-associated secretory phenotype (SASP)-positive nucleus pulposus cells (NPCs) and pro-inflammatory macrophages were considered the most likely primary contributors to this pathological microenvironment. Inspired by these findings, we developed an on-demand collaborative delivery system that concurrently suppresses the SASP in senescent NPCs and reprograms macrophages to attenuate intervertebral disc degeneration. Mechanistically, this delivery system collaboratively reshaped the senescent microenvironment by sustainably releasing interleukin-37 (IL-37) to inhibit SASP progression via the NF-κB pathway and delivering itaconate to macrophages through PLGA nanoparticles to activate the Nrf2 pathway. Notably, this on-demand collaborative delivery system reduced senescence in NPCs from 55.44 ± 2.95% to 5.54 ± 1.35%, achieving a 90% reduction, confirming its efficacy in modulating the senescent microenvironment. Consequently, based on the pathological mechanism, this study proposes a targeted microsphere strategy for senescent microenvironment reconstruction, thereby offering a potential therapeutic avenue for degenerative tissue repair.