Citrus sinensis peel polyphenols loaded alginate nanoparticles: Enhanced stability and anti-diabetic efficacy via bidirectional AMPK regulation and NF-кB suppression.

Citrus sinensis peels are a significant agro-industrial waste generated by the fruit juice industry, which are a rich source of polyphenols with potent therapeutic potential. However, their application is limited due to its low stability and bioavailability. In this present study, a novel alginate-based nanocarrier system was developed for the encapsulation of enriched polyphenols extracted from Citrus sinensis peels (EPCP), using sodium alginate and xanthan gum as biopolymeric carriers. These nanoparticles were comprehensively characterised and evaluated for their encapsulation efficiency, yield, swelling behaviour, release kinetics, bio-accessibility index, and storage stability. In vitro release studies under simulated gastrointestinal conditions revealed a sustained release profile that best fit the Korsmeyer-Peppas model, suggesting a diffusion-controlled mechanism. Long-term stability assessments indicated preservation of biological activities maintained for a year in encapsulated formulations compared to their unencapsulated counterparts. Biological evaluations were performed using RIN-5F pancreatic β-cells and HepG2 hepatocytes. Enriched polyphenols of Citrus sinensis peels loaded alginate nanoparticles (EPCP-ANP) exhibited no cytotoxicity and significantly enhanced insulin secretion while modulating inflammatory responses by suppressing NF-κB activation and promoting anti-inflammatory cytokine expression in streptozotocin induced RIN-5F cells. Furthermore, EPCP-ANP demonstrated bidirectional regulation of AMPK signaling in HepG2 cells across different glucose concentrations, indicating its metabolic regulatory potential. These findings highlight the efficacy of EPCP-ANP as a bioactive delivery system and support its potential as a nanotherapeutic platform for the targeted management of Type 2 Diabetes Mellitus (T2DM). Further in vivo and clinical studies are warranted to validate its therapeutic applicability and safety for translational use.