Injectable microgels carrying engineered biomimetic nanoparticles for osteoarthritis therapy via dual-targeted senescent chondrocyte clearance and endogenous repair promotion - Abstract

Sep 29, 2026

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The accumulation of senescent chondrocytes drives osteoarthritis progression by sustaining a self-perpetuating cartilage-degeneration cycle. Limited precision of existing therapies and lack of coordinated regenerative signaling motivate a new approach. A hydrogel microsphere platform locally eliminates senescent chondrocytes while promoting endogenous repair by combining NKG2D-targeted senolytic ANCM nanoparticles with SDF-1α-loaded regenerative cues for dual-phase action.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages19

Reading Time48 min

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Introduction

Osteoarthritis pathogenesis and cellular senescence

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Keywords and abstract overview

Bioactive Materials 58 (2026) 486–504 Contents lists available at ScienceDirect Bioactive Materials journal [homepage:](homepage: www.keaipublishing.com/en/journals/bioactive-materials)[ www.keaipublishing.com/en/journals/bioactive-materials](homepage: www.keaipublishing.com/en/journals/bioactive-materials) | Injectable microgels carrying engineered biomimetic nanoparticles for osteoarthritis therapy via dual-targeted senescent chondrocyte clearance and endogenous repair promotion | | | | | --- | --- | --- | --- | | Peng Wang a,b,1, Haiyue Zhao a,c,1, Shuo Zhanga,c,1 , Yuhui Guo a, Xin Xinga,
Shuai Zhou a, Shuai Yanga, Fengkun Wang a,c, Wei Chena,*, Juan Wang a,**, Yingze Zhang a,***
a Department of Orthopaedic Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, 050051, China b Fuzhou University Affiliated Provincial Hospital, School of Medicine, Fuzhou University, Fuzhou, 350001, China c School of Medicine, Nankai University, Tianjin, 300071, China | | | | | A R T I C L E I N F O | | A B S T R A C T | | | Keywords: Osteoarthritis Senolysis ABT263
NKG2D
Chondrocyte membrane | | The accumulation of senescent chondrocytes contributes significantly to osteoarthritis (OA) progression, establishing a self-perpetuating cycle of cartilage deterioration. Current therapeutic strategies remain limited by inadequate precision to target senescent populations and the inability to simultaneously trigger endogenous regenerative processes. Herein, we developed a hydrogel microsphere system to locally eliminate senescent chondrocytes, thereby creating a permissive microenvironment and facilitating endogenous stem cell recruitment to accelerate cartilage repair. Specifically, chondrocyte membranes (CM) overexpressing natural killer group 2 member D (NKG2D) receptors (NCM) were fabricated via plasmid transfection and extrusion to target upregulated NKG2D ligands on senescent cells. The fusion of ABT263-loaded liposomes (A-lipo) with NCM produced the senolytic ANCM nanoparticles. Subsequently, ANCM and SDF-1α were co-encapsulated into methacrylic anhydride (MA)-modified hyaluronic acid (HA) hydrogel microspheres (SHM) using microfluidics. The resulting ANCM@SHM exhibited remarkable biocompatibility and a dual-phase functionality: hydrogelenhanced articular retention followed by ANCM-mediated active targeting of senescent chondrocytes. Functional assessments validated the effective clearance of senescent chondrocytes, achieved by inducing mitochondrial outer membrane permeabilization (MOMP), was accompanied by metabolic reprogramming of surviving chondrocytes toward an anabolic phenotype. Simultaneously, sustained SDF-1α release induced robust mesenchymal stromal cells (MSCs) homing and chondrogenic differentiation, resulting in synergistic cartilage remodeling. In vivo evaluations demonstrated a pronounced attenuation of OA progression, attributable to synergistic remodeling of the joint microenvironment. This multidimensional engineering strategy disrupts the vicious cycle of senescence-associated cartilage degeneration by integrating targeted senolysis with stem cellmediated regeneration, providing a promising therapeutic approach for OA management. | | 1. Introduction Osteoarthritis (OA), a common degenerative joint disorder marked by cartilage degradation, synovial inflammation, and subchondral bone remodeling, remains a major cause of disability globally [1]. Despite its high prevalence and substantial impact on quality of life, efficacious disease-modifying treatments for OA remain elusive. Current therapeutic strategies primarily focus on symptom alleviation instead of Peer review under the responsibility of editorial board of Bioactive Materials. * Corresponding author. ** Corresponding author. *** Corresponding author. E-mail addresses: [d202281924@hust.edu.cn](d202281924@hust.edu.cn) (P. Wang), [zhaohaiyue@mail.nankai.edu.cn](zhaohaiyue@mail.nankai.edu.cn) (H. Zhao), [zhang

FAQs

Why are senescent chondrocytes targeted in osteoarthritis therapy?

Senescent chondrocytes accumulate in damaged or aged joints and secrete SASP factors that perpetuate ECM breakdown and inflammatory microenvironments, worsening cartilage degeneration.

How does the system achieve dual-phase therapeutic function?

The hydrogel microspheres provide prolonged joint retention, then deliver NKG2D-targeted senolytic activity to clear senescent chondrocytes while releasing SDF-1α to recruit MSCs and promote chondrogenic differentiation.

What is the mechanism for clearing senescent chondrocytes?

The senolytic nanoparticles induce mitochondrial outer membrane permeabilization (MOMP) in senescent chondrocytes, leading to their effective clearance and metabolic reprogramming toward an anabolic phenotype.

Sep 29, 2026

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