Liraglutide (LIRA) is a glucagon-like peptide-1 (GLP-1) receptor agonist renowned for its efficacy in treating type 2 diabetes mellitus (T2DM) and is typically administered via subcutaneous injections. Oral delivery, although more desirable for being painless and potentially enhancing patient adherence, is challenged by the peptide’s low bioavailability and vulnerability to digestive enzymes. This study aimed to develop LIRA-containing zein-based nanoparticles stabilized with eudragit RS100 and chitosan for oral use (Z-ERS-CS/LIRA). These nanoparticles demonstrated a spherical shape, with a mean diameter of 238.6 nm, a polydispersity index of 0.099, a zeta potential of +40.9 mV, and an encapsulation efficiency of 41%. In vitro release studies indicated a prolonged release, with up to 61% of LIRA released over 24 h. Notably, the nanoparticles showed considerable resistance and stability in simulated gastric and intestinal fluids, suggesting protection from pH and enzymatic degradation. Pharmacokinetic analysis revealed that orally administered Z-ERS-CS/LIRA paralleled the pharmacokinetic profile seen with subcutaneously delivered LIRA. Furthermore, in vivo tests on a diabetic rat model showed that Z-ERS-CS/LIRA significantly controlled glucose levels, comparable to the results observed with free LIRA. The findings underscore Z-ERS-CS/LIRA nanoparticles as a promising approach for oral LIRA delivery in T2DM management.

Silybin (SLB), an important flavonoid from silymarin, displays significant hepatoprotective, anticancer, antioxidant, and neuroprotective effects. However, its therapeutic efficacy is limited by its low solubility and bioavailability. To address these challenges, we engineered bovine serum albumin (BSA) nanoparticles (NP) loaded with SLB (BSA-NP/SLB) using the coacervation method. BSA-SLB NP exhibited a spherical shape, a mean size of 197 nm, a polydispersity index of 0.275, a zeta potential of −34 mV, and an entrapment efficiency of 67%. X-ray diffraction analysis indicated amorphization of SLB upon encapsulation. Formulation stability was upheld over 180 days. In vitro release assays demonstrated controlled diffusion-erosion release, with approximately 40% SLB released within 0.5 h and 100% over 12 h. Intranasal administration of BSA-NP/SLB in rats improved SLB bioavailability by fourfold compared to free SLB. These findings highlight the promising potential of intranasally administered BSA-NP/SLB as an alternative approach to enhance SLB bioavailability, paving the way for innovative therapeutic applications.

Oral delivery of peptide-based therapeutics remains a major challenge due to enzymatic degradation and poor intestinal permeability. This study reports the development of hybrid zein-Eudragit RS100-chitosan nanoparticles for the co-delivery of insulin and liraglutide (Z-ERS-CS/I-LIRA), aiming to protect both peptides and support their oral administration. The nanoparticles were prepared by nanoprecipitation and exhibited suitable physicochemical properties, including nanoscale size (~230 nm), low polydispersity (PDI < 0.1), and positive zeta potential (~ + 46 mV). Structural and thermal analyses (FTIR, XRD, TGA, and DSC) revealed the formation of a predominantly amorphous and molecularly dispersed system, indicating strong interactions among the polymeric components and effective incorporation of both peptides. The formulation remained stable under refrigerated conditions, showed pronounced mucoadhesive behavior after interaction with mucin, and displayed a biphasic release profile in PBS (pH 7.4), with cumulative release values of approximately 87% for insulin and 58% for liraglutide after 48 h. Under simulated gastrointestinal conditions, minimal peptide release (<15%) was observed, suggesting protection against harsh gastric and intestinal environments. In adult zebrafish, unloaded nanoparticles showed no mortality or significant toxicological alterations, supporting preliminary biocompatibility. In a glucose-induced hyperglycemia model, Z-ERS-CS/I-LIRA reduced blood glucose to levels comparable to healthy controls, preserving antidiabetic activity after encapsulation. However, hemorrhagic and pancreatic alterations in liraglutide-containing groups indicate that further liraglutide dose optimization is required to minimize adverse effects. Overall, Z-ERS-CS/I-LIRA combine peptide protection, mucoadhesion, prolonged release, preliminary in vivo biocompatibility, and antidiabetic activity, representing a promising platform for oral peptide-based combination therapy.