A hydrated fibrous gene patch codelivers TGF-β1 siRNA/TAT and berberine for the treatment of peritendinous antiadhesion.

Abstract

Bacterial infections, oxidative stress and inflammatory responses after tendon surgery are highly associated with peritendinous adhesion formation. Although drug-loaded anti-adhesion barriers have been extensively studied, most of them lack control over the process of drug release from the anti-adhesion barrier and fail to coordinate with the tendon's own biological mechanisms. Here, inspired by the mechanisms of tendon adhesion development, an anti-peritendon adhesion hydrated fibrous gene patch with antimicrobial antioxidant and anti-inflammatory activity was developed. First, hydrazinylated hyaluronic acid and dialdehyde polyethylene glycol were crosslinked to prepare a self-healing hydrogel (DHP). Then, the hydrogel loaded with transforming growth factor-β1 siRNA/TAT conjugate was attached to a Poly(L-lactide-co-ε-caprolactone) electrospun fiber membrane containing berberine to form a composite bilayer patch. The encapsulated TGF-β1 siRNA complex in the siRNA@DHP-PB patch responds to the microenvironment by releasing to the outer gel side, blocking the key fibrosis pathway and inhibiting the formation of tendon adhesion tissue; the loaded Ber is released to the inner fiber side, with antioxidant, anti-inflammatory and antimicrobial properties, providing a good microenvironment for tendon regeneration. This design fills the therapeutic gap between transient anti-inflammatory treatment and delayed antifibrotic intervention, offering a paradigm shift in the field of regenerative medicine that transcends tendon repair and holds potential for chronotherapeutic applications and multimodal anti-adhesion strategies. STATEMENT OF SIGNIFICANCE: Peritendinous adhesions are a critical post-tendon-injury complication. Conventional anti-adhesion barriers (e.g., drug-loaded hydrogels/fibers) lack microenvironment-responsive drug control and tendon-specific biointegration. We developed a multifunctional siRNA@DHP-PB patch with antimicrobial, antioxidant, and anti-inflammatory properties. Its outer layer is a self-healing hydrogel (crosslinked hydrazide-hyaluronic acid/aldehyde-polyglycol) encapsulating TGF-β1 siRNA/TAT, while the inner PLCL electrospun membrane is loaded with berberine. The siRNA complex is released toward the gel interface to suppress early-stage inflammatory TGF-β1, minimizing tendon toxicity. Berberine, released at the fiber interface, scavenges ROS, prevents infections, and inhibits oxidative damage. This bidirectional, biodegradable system enables targeted, adhesion-free tendon repair.