Multiscale characterization of ultrasmall fluorescent core-shell silica nanoparticles in cartilage and synovial joints reveals rapid cartilage penetration and sustained joint residence.

Development of non-surgical disease-modifying interventions for knee osteoarthritis (OA) remains a persistent challenge despite decades of efforts. Therapeutic transport to cartilage in synovial joints is hindered by the dense, negatively charged cartilage matrix, and further challenged by rapid synovial fluid clearance within hours to days. In this study, we investigated ultrasmall (d ∼ 6 nm) fluorescent core-shell silica nanoparticles (Cornell Prime Dots, or C' Dots), which have received FDA-investigational new drug approval for multiple human clinical trials in oncology, as cartilage-penetrating delivery vehicles for applications in knee OA. Across multiple length and time scales, we examined the relationship between C' Dot tissue and cellular transport kinetics and whole joint clearance. In vitro, C' Dots penetrated cartilage explants within 30 min (D ∼ 2 µm/s). C' Dots were internalized by chondrocytes within 24 h and were retained in vesicular structures for up to 5 days. In vivo, C' Dot clearance following intra-articular knee injection was well described by two distinct time constants (τ ∼ 18 hours, τ ∼ 3 weeks), consistent with mechanisms of synovial- and tissue-mediated clearance. C' Dot clearance rates were not affected by surgically-induced cruciate ligament transection. Notably, C' Dots remained in the knee longer than 3 months after a single injection and were localized to cartilage, meniscus, ligaments, and synovium. Collectively, these results illustrate the potential of C' Dots for long-term delivery of conjugated therapeutics in the knee. STATEMENT OF SIGNIFICANCE: This research explores a cartilage-penetrating platform nanotechnology for applications in drug delivery for arthritis. The properties inherent to this particle system enabled rapid tissue penetration, chondrocyte internalization and retention, and persistence in rat knees for longer than 3 months after a single injection. The study demonstrates that ultrasmall nanoparticle delivery platforms can use tissue localization to partially avoid clearance by the synovium, while simultaneously enabling chondrocyte targeting. When paired with a therapeutic, C' Dots may be a versatile platform in early-stage OA and PTOA to protect cartilage from further degeneration. These findings inform future design and engineering of biocompatible drug delivery vehicles for other applications where access to dense tissues is needed.