Synovial macrophage-targeted hierarchical microspheres achieve cartilage preservation and pain relief in osteoarthritis
Mater Today Bio. 2026 May 22;38:103178. doi: 10.1016/j.mtbio.2026.103178. eCollection 2026 Jun.
ABSTRACT
Pain, the hallmark symptom of osteoarthritis (OA), drives most patients to seek medical care. The current analgesics only provide partial pain relief, while fail to modify disease progression and introduce adverse effects with long-term use. Therefore, elucidating the underlying causes of OA-related pain and developing etiology-targeted therapeutics are urgently needed. In this research, we discovered that M1 macrophages and Netrin-1 are highly co-located in the synovium of both OA patients and anterior cruciate ligament transection (ACLT) mice. Moreover, depletion of macrophages in the knee of ACLT mice significantly alleviated OA pain. Thus, it is hypothesized that modulating synovial macrophage polarization may alleviate OA pain by regulating Netrin-1. Based on these findings, we designed Tof@HA-TAGel-an injectable hydrogel microsphere that selectively targets synovial macrophages and enables the sustained release of both tannic acid (TA) and tofacitinib (Tof). Experimental results demonstrated that Tof@HA-TAGel scavenges reactive oxygen species (ROS), suppress M1 macrophage polarization and attenuates cytokine storm through downregulating the JAK-STAT pathway, thereby reducing Netrin-1 secretion and inhibiting sensory nerve ingrowth. In ACLT-induced OA models, the microsphere significantly attenuated cartilage degradation. Behavioral assessments (Gait analysis, Von Frey tests) confirmed pain alleviation and functional recovery. Immunofluorescence further revealed suppressed M1 infiltration, diminished Netrin-1, and reduced Calcitonin Gene-Related Peptide (CGRP) nerve ingrowth in synovium. Collectively, Tof@HA-TAGel integrates anti-inflammatory, antioxidant, and analgesic mechanisms. This multifunctional system mitigates OA pain by inhibiting synovial macrophage polarization and subsequent sensory nerve ingrowth while protecting cartilage concurrently. It positions a promising disease-modifying biomaterial for etiology-aware OA therapy.
PMID:42238956 | PMC:PMC13227287 | DOI:10.1016/j.mtbio.2026.103178