By responding to disease-linked enzymes at two different stages, the hydrogel-nanocapsule system keeps bFGF in the joint longer and delivers it deeper into damaged cartilage.
Paper: Programmable hydrogel-nanocapsule protein delivery system targeting dense cartilage regeneration for osteoarthritis therapy. Image Credit: Ople Witsanu / Shutterstock
*Important notice: This news reports on an unedited version of an accepted paper and is awaiting final editing. Therefore, the paper should not be regarded as conclusive or treated as established information.
A recent paper in the journal Nature Communications reported the development of hydro/nano-bFGF, a programmable system that combines a basic fibroblast growth factor (bFGF)-loaded nanocapsule (nano-bFGF) with a cartilage-adhesive, injectable hydrogel for cartilage regeneration in osteoarthritis.
Limitations of existing treatments
Osteoarthritis, a major cause of medical costs and disability, affects more than 500 million people worldwide. Intra-articular administration is a common approach to treating this degenerative joint disease.
However, these pharmacological treatments mainly provide short-term relief from osteoarthritis symptoms and do not prevent cartilage degeneration. Researchers have considered many proanabolic biologic agents for osteoarthritis treatment, including transforming growth factor β (TGF-β) and FGFs.
Clinical studies have investigated direct intra-articular delivery of such agents, but evidence of sustained efficacy or meaningful cartilage effects remains limited. The paper notes that the highest dose of sprifermin, a recombinant human FGF18, showed statistically significant structural effects in a later trial, but its clinical importance remained uncertain.
Challenges in chondrocyte-targeted drug delivery
The researchers identify insufficient drug delivery to chondrocytes as a major reason for limited bioactivity. The first obstacle is retaining drugs within the joint.
Drugs injected directly into the joint have short residence times because sub-synovial capillaries or lymphatics rapidly clear soluble agents from the cartilage surface.
The second obstacle is penetration through the cartilage matrix. Chondrocytes are distributed in a dense, avascular extracellular matrix (ECM) and are the only resident cell type within cartilage.
The ECM acts as a significant diffusional and steric barrier. It limits the movement of therapeutic agents from synovial fluid into cartilage and their later internalization by chondrocytes, while also protecting the cells.
A more effective delivery system is needed to support prolonged therapy and increase bioactivity by addressing poor cartilage penetration, rapid synovial clearance, and the infection risk associated with frequent intra-articular administration.
The proposed programmable system
The researchers developed hydro/nano-bFGF to support cartilage regeneration by delivering and sustaining therapeutic protein release more efficiently. The system combines an FGF-loaded nanocapsule with an injectable, cartilage-adhesive hydrogel.
Osteoarthritic cartilage degeneration is linked to increased activity of matrix metalloproteinases (MMPs), including membrane-associated membrane-type 1 (MT1)-MMP at the chondrocyte surface and soluble MMP13 in the cartilage microenvironment and synovial fluid.
These spatially distinct pathological cues motivated the enzyme-responsive design.
The system contains two coordinated modules: a nanocapsule designed to penetrate cartilage and release protein near the chondrocyte surface, and a cartilage-adhesive injectable hydrogel designed for drug retention and disease-responsive release.
The team selected human recombinant bFGF as the model therapeutic protein. First, the team formulated the bFGF-loaded nanocapsule by tailoring the polymerization of enzyme-cleavable crosslinkers, neutral monomers, and cationic monomers on the protein surface.
Next, the researchers formed the injectable hydrogel by co-injecting an MMP13-sensitive crosslinker and nano-bFGF with maleimide-functionalized hyaluronic acid (HA-Mal), producing the hydrogel-encapsulated nano-bFGF formulation called hydro/nano-bFGF.
After injection, the thiol-maleimide reaction mediated hydrogel formation and adhesion to the cartilage surface.
Hydro/nano-bFGF formulation: The researchers prepared separate HA-Mal and MMP13-cleavable crosslinker/nano-bFGF solutions in phosphate-buffered saline. They co-injected equal volumes, allowing the hydrogel to form in situ within the joint cavity and adhere to the cartilage surface.
Effectiveness of the programmable system
The authors generated nano-bFGF through interfacial polymerization of monomers with enzyme-cleavable crosslinkers on the protein surface, forming a nanoscale shell that preserved bioactivity and enabled pathology-specific disassembly. They note that the integrity of the complete nanocapsule under physiologically relevant conditions still requires direct study.
The hydrogel anchored nano-bFGF to the cartilage surface and gradually degraded within the joint, breaking down faster under osteoarthritis-associated conditions. This staged release prolonged local retention, supported transport into cartilage, and maintained growth factor function.
As the MMP13-responsive hydrogel degraded, it freed nanocapsules near the cartilage surface. MT1-MMP-responsive nanocapsules then disassembled near chondrocytes, releasing bFGF in the pericellular region.
The released bFGF could engage nearby FGF receptors, promote chondrocyte anabolic activity, and increase ECM synthesis, which could support restoration of cartilage thickness in osteoarthritis.
Simulation and human explant studies indicated that greater cartilage penetration is linked to nano-bFGF size and positive surface charge.
The finite-element model did not reproduce every feature of a living joint, including synovial clearance, cyclic compression, and fluid convection during movement.
In human osteoarthritic cartilage explants, nano-bFGF increased glycosaminoglycan deposition by about 200% relative to untreated explants and produced about threefold higher type II collagen expression than free bFGF treatment.
In rats with osteoarthritis induced by anterior cruciate ligament transection (ACLT), researchers injected the treatment once every two weeks for eight weeks. Hydro/nano-bFGF improved cartilage integrity, restored cartilage thickness toward the sham-operated level, improved subchondral bone architecture, and produced better locomotor performance than control treatments.
In a separate mouse knee imaging experiment, the formulation prolonged the measured intra-articular half-life of bFGF to 10.10 days, compared with 3.96 days for nano-bFGF and about 0.16 hours for free bFGF.
The paper also notes that bFGF can have context-dependent effects on cartilage. Under the tested dose and delivery conditions, the researchers observed no obvious chondrocyte clustering and found lower IL-1β, IL-6, and MMP13 expression in treated rat cartilage. These findings apply only to the experimental conditions studied and do not establish safety at other doses or in other treatment settings.
The researchers propose adapting the strategy to other degenerative joint diseases and protein therapeutics because of its modular design, but they did not test those broader applications in this study.
The eight-week rat experiments showed no obvious major-organ histological abnormalities or serum evidence of liver or kidney dysfunction under the tested conditions, but long-term biodegradation, intra-articular persistence, clearance, chronic toxicity, and possible cumulative tissue effects remain unresolved.
The system has not been tested in human patients, and the human cartilage experiments used explanted tissue outside the body.
The authors call for large-animal studies with joint biomechanics and cartilage thickness closer to those in humans before clinical translation can be assessed.
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Source:
- Zhu, Q. et al. (2026). Programmable hydrogel-nanocapsule protein delivery system targeting dense cartilage regeneration for osteoarthritis therapy. Nature Communications. DOI: 10.1038/s41467-026-79166-5, https://www.nature.com/articles/s41467-026-79166-5