Preparation and Evaluation of Photothermally Responsive Triptolide Composite Gel for Treating Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a prevalent chronic systemic autoimmune disease that induces irreversible joint erosion and disability. Triptolide (TP) exerts potent therapeutic efficacy against RA. However, conventional transdermal TP formulations provoke severe skin irritation upon long-term application, substantially restricting their clinical translation. To overcome these limitations, we fabricated water-stable cross-linked γ-cyclodextrin metal-organic frameworks (COFs) for TP encapsulation and synthesized phospholipid-modified polypyrrole nanoparticles (PPy-PC NPs) with outstanding photothermal performance. A composite hydrogel designated TP@COF-PPy NPs gel was constructed to integrate photothermal therapy (PTT) and transdermal delivery, enabling synergistic RA intervention with lowered systemic and cutaneous toxicity. The composite gel afforded a TP loading capacity of (454.81 ± 40.17) μg/g, accompanied by favorable structural stability, excellent photothermal properties and satisfactory rheological characteristics. In vitro release experiments revealed that the gel displayed a unique biphasic release profile and compensated for the inadequate late-stage drug leakage of pure TP gel. Notably, PTT irradiation neither damaged the gel structure nor induced abrupt drug burst release. In vitro transdermal assays verified that the optimized gel boosted cutaneous permeation, diminished skin drug retention, and facilitated deep-tissue drug penetration; auxiliary PTT further elevated permeation efficiency and mitigated skin toxic responses. Pharmacological evaluations confirmed that the composite gel halted RA progression via suppressing inflammatory cascades, modulating bone destruction and restoring immune homeostasis. The gel combined with PTT yielded markedly superior therapeutic outcomes relative to the gel monotherapy and clinical positive agents (methotrexate, diclofenac sodium). Biosafety assessments validated that the combinatorial regimen possessed superior skin biocompatibility, and no obvious hepatic, renal, or reproductive toxicities were detected in collagen-induced arthritis rats following 30-day continuous administration. Collectively, this study proves that PTT-augmented transdermal TP delivery represents a safe, promising strategy for efficient RA management.