# Programmable Macrophage Mimics for Inflammatory Meniscus Regeneration via Nanotherapy

## TL;DR

This paper introduces programmable macrophage mimics that reduce inflammation and promote meniscus regeneration in knee injuries.

## Contribution

The study presents a novel bifunctional nano-delivery system for sequential anti-inflammatory and regenerative therapy in meniscal injuries.

## Key findings

- PMMs effectively adsorb proinflammatory cytokines and release growth factors to promote stem cell differentiation.
- ADSC-loaded PMMs@mGC hydrogels showed significant fibrocartilage regeneration in rabbit osteoarthritis models.
- A 3D-printed framework was developed for total meniscus replacement using the PMMs@mGC system.

## Abstract

Meniscal injuries are common in the knee joint. Minor meniscal injuries usually respond well to conservative treatment, while severe cases often require complete meniscal replacement. Meniscal injuries cause inflammatory responses that importantly hinder meniscal tissue regeneration. Despite ongoing advances in research, considerable breakthroughs in meniscal regeneration remain out of reach. This study introduces programmable macrophage mimics (PMMs), which enable sequential regulation from anti-inflammatory responses to meniscal fibrocartilage regeneration. PMMs were prepared by encapsulating the transforming growth factor-β3 and insulin-like growth factor-1 growth factors within mesoporous silica nanoparticles modified with branched polyethyleneimine via disulfide bonding. This design allows the initial adsorption of proinflammatory cytokines followed by the controlled release of growth factors that promote adipose-derived stem cell (ADSC) differentiation into fibrochondrocytes. The PMMs were integrated into meniscus-specific acellular matrix hydrogels (mGC), which provided suitable mechanical properties critical for effective regeneration. In rabbit osteoarthritis models, ADSC-loaded PMMs@mGC hydrogels showed marked fibrocartilage regeneration. Additionally, the team developed an advanced biofabrication approach that combines a 3-dimensionally printed polycaprolactone framework designed for total meniscus replacement. This research suggests that PMMs act as a bifunctional “core–shell” nano-delivery system, offering a promising therapeutic strategy for managing inflammatory meniscal conditions.