Engineering oral celastrol-polysaccharide supramolecular nanoassemblies across intestinal barriers for the intervention of nonalcoholic steatohepatitis

The development of effective oral therapies for nonalcoholic steatohepatitis (NASH) remains a critical unmet need in clinical practice. Celastrol (CEL), a potent natural compound, is a promising candidate for NASH due to its lipid-modulating, anti-inflammatory properties, and antioxidative properties. However, its clinical translation is severely hindered by poor oral bioavailability and a narrow therapeutic window stemming from significant toxicity. To overcome these limitations, we present the design and fabrication of novel, carrier-free CEL nanoparticles stabilized through natural polysaccharide self-assembly. This innovative formulation strategy is aimed at substantially enhancing the oral bioavailability of CEL, thereby augmenting its therapeutic efficacy in NASH while mitigating associated adverse effects. In this study, we developed a polysaccharide-CEL supramolecular depot comprising 42 distinct nanoassemblies for oral delivery in NASH, identifying chondroitin sulfate (CS) as the optimal polysaccharide adjuvant. The resulting CS/CNA formulation dramatically improved oral absorption, achieving a 3.12-fold higher bioavailability than free CEL in pharmacokinetic studies. Mechanistic investigations revealed that CS/CNA crosses the intestinal barrier via multiple endocytosis pathways and successfully evades lysosomal degradation. In a murine model of NASH, CS/CNA demonstrated potent therapeutic efficacy by modulating hepatic inflammation and reducing lipid accumulation. Critically, the nanoassembly exhibited an excellent safety profile, mitigating the toxicity associated with free CEL. By enhancing therapeutic efficacy while reducing adverse effects, this strategy effectively widens the therapeutic window for celastrol. This work establishes CS/CNA as a promising oral therapeutic candidate and provides a robust platform for advancing the clinical potential of CEL for NASH management.