Chondrocyte-targeted bilirubin/rapamycin carrier-free nanoparticles alleviate oxidative stress and modulate autophagy for osteoarthritis therapy

Abstract

Osteoarthritis (OA) is a prevalent chronic disease, characterized by the destruction of joint cartilage and synovitis, affects over 7 % of people worldwide. Disease-modifying treatments for OA still face significant challenges. Chondrocytes, as the exclusive cellular component of articular cartilage, play a pivotal role in synthesizing the intricate matrix of cartilage, thereby assuming a critical responsibility in facilitating its renewal and repair processes. However, oxidative stress within chondrocytes and subsequent apoptotic cell death plays significant roles in the progression of OA. Therefore, targeting apoptosis inhibition and mitigation of oxidative stress in chondrocytes represents a promising therapeutic strategy for OA. This study develops a type II collagen-targeting peptide (WYRGRLC) modified bilirubin/rapamycin carrier-free nanoparticle (PP/BRRP) and evaluate its therapeutic potential for OA. The PP/BRRP system exhibits remarkable chondrocyte-targeting ability, enabling the rupture of highly oxidized chondrocytes and subsequent release of bilirubin and rapamycin. This dual payload effectively scavenges reactive oxygen species, triggers autophagy, and suppresses the mTOR pathway, thereby augmenting anti-inflammatory and anti-apoptotic effects. The in vivo experiments further validate the retention and therapeutic efficacy of PP/BRRP in rat joints affected by OA. Overall, PP/BRRP exhibits significant potential for intervention and treatment of OA.

Keywords: Apoptosis; Autophagy; Bilirubin; Chondrocytes; Osteoarthritis; Rapamycin.