| Cell- and Tissue-Culture Approaches (Senolytics) |
Dasatinib + Quercetin (D+Q) |
BCR-ABL/Src inhibition + flavonol synergy; selectively induces apoptosis of senescent chondrocytes |
Single intra-articular dose cleared p16ˆNK4aˆ+ cells and reduced cartilage loss in DMM mice (Jeon et al., 2017) |
Pre-clinical proof-of-concept; off-target toxicity with systemic delivery |
|
Navitoclax (ABT-263) |
BCL-2/BCL-xL inhibition; intrinsic apoptotic activation in SnCs |
Weekly IA injections attenuated degeneration and improved gait in DMM rats (Li et al., 2018) |
Pre-clinical; dose-limiting thrombocytopenia hampers systemic use |
|
Fisetin |
Flavonol that disrupts pro-survival pathways in SnCs; antioxidant |
Reduced SASP markers and pain in PTOA mice; Phase I knee-OA trial ongoing (NCT04770064) |
Early clinical safety evaluation; efficacy yet to be proven |
| Cell- and Tissue-Culture Approaches (Senomorphics) |
Tofacitinib (pan-JAK inhibitor) |
Suppresses SASP via JAK/STAT blockade without killing senescent cells |
In vitro: ↓ IL-6, MMP-13 in OA chondrocytes; ex vivo human cartilage |
FDA-approved for RA; immunosuppression risk in chronic use |
| Small-Animal PTOA Models |
Rapamycin |
mTOR inhibition; SASP suppression and autophagy activation |
Intra-articular rapamycin lowered SASP factors and preserved cartilage post-injury (Nogueira-Recalde et al., 2019) |
Pre-clinical; systemic use limited by immunosuppression |
| Nanoparticle-Based Delivery Systems |
Folate-ZnO NPs |
Metabolic targeting of inflammatory senescent macrophages; enhanced uptake (∼40%) |
Inflammatory senescent macrophages in PTOA models (Dey et al., 2021) |
Pre-clinical; safety profile under evaluation |
|
PEG-grafted lipid NPs (CRISPR-Cas + hydrophobic drugs) |
Co-delivery platform; sustained intra-articular release >48 h |
PTOA-relevant nanodelivery proof-of-concept (Ansari et al., 2023) |
Pre-clinical; manufacturing complexity |
| Monoclonal-Antibody Platforms |
Anti-uPAR ADC |
Antibody–drug conjugate |
Complete clearance ex vivo; entering first-in-human dose-escalation (Ro et al., 2024) |
Early clinical; potential “senolytic crisis” |
|
Anti-IL-1β mAb (Canakinumab) |
Neutralises SASP driver cytokine IL-1β |
ACLT rabbit knees: reduced MMP activity and cartilage erosion (Wang, Lankhorst & Bernards, 2022) |
Phase III CV trials show safety; high cost; systemic dosing |
| Combined Regenerative + Anti-senescence |
MSCs over-expressing α-Klotho |
Paracrine anti-SASP signals; cartilage matrix repair |
Rat PTOA model: restored cartilage thickness, ↓ p16ˆINK4aˆ staining (Zhang et al., 2025) |
Pre-clinical; manufacturing & regulatory complexity |
