Dual-responsive gelatin-based amphiphilic Celastrol prodrug polymer nanoassemblies for psoriasis treatment

Celastrol (CE) has been investigated for its prophylactic and anti-inflammatory effects in various inflammatory and autoimmune diseases like psoriasis. However, poor water solubility, low bioavailability, and high toxicity have limited its application The objective of this study is to design and synthesize a gelatin-based CE prodrug polymer which can self-assemble into nanoparticles, encapsulating CE to improve its aqueous solubility. Two gelatin derivatives with opposite charges were synthesized through a condensation reaction. CE prodrug nanoparticles were formed by coupling CE to these two gelatin derivatives using dynamic chemical bonding: C-S bonds and borate bonds. The resulting nanoparticles(G-C-G) had an average particle size of approximately 147.15 ± 8.25 nm, and a drug loading capacity of 1.52 ± 0.25%. The transdermal penetration of nanoparticles (G-C-G) was found to be improved compared to free CEin vitro. In a mouse model of psoriasis, nanoparticles G-C-G resulted in a reduction of erythema, scaly epidermal symptoms, spleen weight, and cytokine levels, including IL-17 and IL-23, indicating high therapeutic potential for psoriasis. In conclusion, CE prodrug nanoparticles (G-C-G) increase the water solubility and skin permeability of free CE, making it a potential therapeutic agent for psoriasis.