Novel pH-responsive lipid nanoparticles deliver UA-mediated mitophagy and ferroptosis for osteoarthritis treatment

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Rheumatology

Background:

• Synovial inflammation is central to osteoarthritis (OA) pathogenesis, causing chronic inflammation and cartilage damage.
• Current OA treatments targeting synovitis show limited efficacy due to poor drug delivery and joint heterogeneity.

Purpose of the Study:

• To develop and evaluate pH-responsive lipid nanoparticles loaded with Urolithin A (LNPs@UA) as a targeted therapy for osteoarthritis.
• To assess the in vitro and in vivo efficacy of LNPs@UA in mitigating OA progression.

Main Methods:

• Characterization of LNPs@UA for particle size, zeta potential, mitochondria-targeting, and pH-responsiveness.
• In vitro assessment of LNPs@UA effects on reactive oxygen species (ROS), pro-inflammatory cytokines, macrophage polarization, mitochondrial function, autophagy, and ferroptosis.
• In vivo evaluation of LNPs@UA in an ACLT-induced OA mouse model, including transcriptomic analysis.

Main Results:

• LNPs@UA demonstrated uniform size, low zeta potential, and effective mitochondria-targeting and pH-responsive drug release.
• In vitro studies showed LNPs@UA reduced ROS and pro-inflammatory factors (IL-1β, IL-6, TNF-α), promoted M2 macrophage polarization, improved mitochondrial structure, enhanced autophagy, and inhibited ferroptosis.
• In vivo, LNPs@UA significantly alleviated OA progression, with transcriptomic analysis indicating NF-κB pathway inhibition and activation of repair pathways.

Conclusions:

• LNPs@UA represent a novel, targeted therapeutic strategy for osteoarthritis.
• The pH-responsive and mitochondria-targeting properties of LNPs@UA enhance their efficacy in managing OA-related inflammation and cartilage destruction.