Chitosan-coated and sodium phytate-crosslinked porous starch microspheres for oral delivery of celastrol in colitis therapy.

Abstract

Inflammatory bowel disease (IBD), particularly ulcerative colitis (UC), imposes a growing clinical burden worldwide. Celastrol (Cel), a potent anti-inflammatory triterpenoid, holds considerable promise for UC treatment but is severely constrained by its poor water solubility and low oral bioavailability. Porous starch (PS) offers an attractive drug reservoir for oral delivery yet suffers from low drug loading capacity and structural instability. To address these limitations, we constructed a C-Sp-PS/Cel microsphere delivery system by modifying enzymatic hydrolyzed PS via sodium phytate (Sp) crosslinking and coating with chitosan(CS). The PS core provided a high surface area for drug loading. Sp crosslinking simultaneously enhanced Cel loading capacity to 24.88 ± 0.20 mg/g (1.9-fold over unmodified PS) and conferred retrogradation resistance, while the CS coating effectively suppressed premature drug release. At the cellular level, C-Sp-PS/Cel recovered mitochondrial membrane potential in inflamed macrophages, confirming dual protection against both oxidative stress and mitochondrial depolarization. In a dextran sulfate sodium (DSS)-induced murine colitis model, oral C-Sp-PS/Cel treatment restored colon length and spleen index to levels comparable to healthy controls, reduced F4/80+ macrophage infiltration, and restored tight junction proteins (ZO-1, Occludin, Claudin-4) to near-baseline levels. 16S rRNA sequencing confirmed the formulation indirectly restored gut microbiota homeostasis by alleviating inflammation, enriching Muribaculaceae and suppressing Parabacteroides. This study presents a natural polysaccharide platform that synergistically integrates a porous reservoir, polyanion-mediated crosslinking, and cationic mucoadhesive coating to achieve dual protection for targeted oral delivery of poorly soluble therapeutics in intestinal inflammation.