An intelligent insulin delivery system is highly desirable for diabetes management. Herein, we developed a novel glucose-responsive multivesicular liposome (MVL) for self-regulated insulin delivery using the double emulsion method. Glucose-responsive MVLs could effectively regulate insulin release in response to fluctuating glucose concentrations in vitro. Notably, in situ released glucose oxidase catalyzed glucose enrichment on the MVL surface, based on the combination of (3-fluoro-4-((octyloxy)carbonyl)phenyl)boronic acid and glucose. The outer MVL membrane was destroyed when triggered by the local acidic and H₂O₂-enriched microenvironment induced by glucose oxidase catalysis in situ, followed by the further release of entrapped insulin. Moreover, the Alizarin red probe and molecular docking were used to clarify the glucose-responsive mechanism of MVLs. Utilizing chemically induced type 1 diabetic rats, we demonstrated that the glucose-responsive MVLs could effectively regulate blood glucose levels within a normal range. Our findings suggest that glucose-responsive MVLs with good biocompatibility may have promising applications in diabetes treatment.

In recent years, pneumonia caused by multiple viruses has posed a significant threat to public health, particularly affecting vulnerable populations such as the elderly and immunocompromised individuals. Current treatments primarily focused on antiviral medications, lacking “miracle cure” and innovative approaches for the pathological damage caused by viruses. Since 2019, Traditional Chinese Medicine (TCM) has shown remarkable efficacy in treating coronavirus disease 2019 (COVID‐19). However, the application is hindered by intricate mechanisms, variable quality, and slow onset. Clinically, Ge‐Gen Decoction (GGD) effectively reduced the severity in patients with viral infections. Taking COVID‐19 as a case, the bioactive ingredients from GGD: glabridin (GLA) and puerarin (PUE) are identified. Interestingly, it was discovered that PUE can self‐assemble into a 3D hydrogel structure upon heating and cooling, namely PUE@gel. This process mirrored the formation of gel‐like precipitates in GGD post‐decoction. Motivated by this phenomenon, a decoction‐mimicking drug delivery system, glabridin─puerarin self‐assembled hydrogel (GLA‐PUE@gel) was constructed, which exhibits strong anti‐inflammatory and antioxidant properties, comparable to GGD at the same dosage. Additionally, PUE that has a high biosafety threshold can competitively bind to angiotensin converting enzyme 2 (ACE2) on host cells, preventing SARS‐CoV‐2 from invading. This study offered a promising approach for treating virus‐induced lung injury.

Background: Diabetes has become a serious global public health problem. With the increasing prevalence of type 2 diabetes mellitus (T2DM), the incidence of complications of T2DM is also on the rise. Sitagliptin, as a targeted drug of DPP4, has good therapeutic effect for T2DM. It is well known that sitagliptin can specifically inhibit the activity of DPP4 to promote insulin secretion, inhibit islet β cell apoptosis and reduce blood glucose levels, while other pharmacological mechanisms are still unclear, such as improving insulin resistance, anti-inflammatory, anti-oxidative stress, and anti-fibrosis. The aim of this study was to explore novel targets and potential signaling pathways of sitagliptin for T2DM.Methods: Firstly, network pharmacology was applied to find the novel target most closely related to DPP4. Semi-flexible molecular docking was performed to confirm the binding ability between sitagliptin and the novel target, and molecular dynamics simulation (MD) was carried to verify the stability of the complex formed by sitagliptin and the novel target. Furthermore, surface-plasmon resonance (SPR) was used to explored the affinity and kinetic characteristics of sitagliptin with the novel target. Finally, the molecular mechanism of sitagliptin for T2DM was predicted by the enrichment analysis of GO function and KEGG pathway.Results: In this study, we found the cell surface receptor―angiotensin-converting enzyme 2 (ACE2) most closely related to DPP4. Then, we confirmed that sitagliptin had strong binding ability with ACE2 from a static perspective, and the stability of sitagliptin―ACE2 complex had better stability and longer binding time than BAR708―ACE2 in simulated aqueous solution within 50 ns. Significantly, we have demonstrated a strong affinity between sitagliptin and ACE2 on SPR biosensor, and their kinetic characteristics were “fast binding/fast dissociation”. The guiding significance of clinical administration: low dose can reach saturation, but repeated administration was needed. Finally, there was certain relationship between COVID-19 and T2DM, and ACE2/Ang-(1-7)/Mas receptor (MasR) axis may be the important pathway of sitagliptin targeting ACE2 for T2DM.Conclusion: This study used different methods to prove that ACE2 may be another novel target of sitagliptin for T2DM, which extended the application of ACE2 in improving diabetes mellitus.

Although nanoparticles (NPs) have emerged as a promising strategy to improve oral absorption of insulin, most of them still have minimal oral bioavailability due to the harsh gastrointestinal (GI) environment and epithelial barriers. A novel platform of oral insulin delivery is herein proposed based on amphiphilic cholesterol-phosphate conjugate (CHP). The CHP was synthesized with a cholesterol moiety as a hydrophobic block and a phosphate group as a hydrophilic block. The structural characteristics of CHP made cholesteryl moieties to point outward to form a shell coated on the surface of NPs, and phosphate groups toward inside as the core via the water-in-oil (W/O) emulsion method. The additional Ca²⁺ could chelate to phosphate groups in the core to bind adjacent phosphate groups and further increased the stability of NPs (CP-Ca NPs). Phospholipid and glycocholate were modified on the surface of CP-Ca NPs to form hydrophilic corona coated CP-Ca NPs (Hc@CP-Ca NPs) and didn't change the structure of CP-Ca NPs. The NPs exhibited high encapsulation efficiency (>95%) and had high stability in the GI tract by reducing insulin release and protecting insulin from enzymatic degradation. Compared to free insulin, Hc@CP-Ca NPs demonstrated 31-fold higher cellular uptake in Caco-2 cells for 1 h incubation. Furthermore, the transepithelial transport efficiency of Hc@CP-Ca NPs was 12-fold higher than that of free insulin. Moreover, CP-Ca NPs and Hc@CP-Ca NPs generated a rapid-onset and long-lasting hypoglycemic effect following gavage in type 1 diabetic mellitus (T1DM) rats. The pharmacological activity and the relative bioavailability were increased to 13.5% and 12.2%, respectively. Thus, these results indicated that CHP assembled NPs may provide a promising potential for oral insulin delivery by protection and absorption promotion.