Glucose-Responsive Self-Regulated Injectable Silk Fibroin Hydrogel for Controlled Insulin Delivery

Stimuli-responsive drug delivery systems are gaining importance in personalized medicine to deliver therapeutic doses in response to disease-specific stimulation. Pancreas-mimicking glucose-responsive insulin delivery systems offer improved therapeutic outcomes in the treatment of type 1 and advanced stage of type 2 diabetic conditions. Herein, we present a glucose-responsive smart hydrogel platform based on phenylboronic acid-functionalized natural silk fibroin protein for regulated insulin delivery. The modified protein was synergistically self-assembled and cross-linked through β-sheet and phenylboronate ester formation. The dynamic nature of the bonding confers smooth injectability through the needle. The cross-linked hydrogel structures firmly hold the glucose-sensing element and insulin in its pores and contribute to long-term sensing and drug storage. Under hyperglycemic conditions, the hydrogen peroxide generated from the sensing element induces hydrogel matrix degradation by oxidative cleavage, enabling insulin release. In vivo studies in a type 1 diabetic Wistar rat model revealed that the controlled insulin release from the hydrogel restored diabetic glucose level to physiological conditions for 36 h. This work establishes the functional modification of silk fibroin into a glucose-responsive hydrogel platform for regulated and functional insulin delivery application

Intrinsically Disordered Ku Protein-Derived Cell-Penetrating Peptides

Efficient delivery of bioactive ingredients into cells is a major challenge. Cell-penetrating peptides (CPPs) have emerged as promising vehicles for this purpose. We have developed novel CPPs derived from the flexible and disordered tail extensions of DNA-binding Ku proteins. Ku-P4, the lead CPP identified in this study, is biocompatible and displays high internalization efficacy. Biophysical studies show that the proline residue is crucial for preserving the intrinsically disordered state and biocompatibility. DNA binding studies showed effective DNA condensation to form a positively charged polyplex. The polyplex exhibited effective penetration through the cell membrane and delivered the plasmid DNA inside the cell. These novel CPPs have the potential to enhance the cellular uptake and therapeutic efficacy of peptide-drug or gene conjugates

Multifunctional Architectures of Cyclic Dipeptide Copolymers and Composites, and Modulation of Multifaceted Amyloid‑β Toxicity

Alzheimer’s disease (AD) is a major neurodegenerative disorder primarily characterized by the β-amyloid (Aβ42) misfolding and aggregation-associated multifaceted amyloid toxicity encompassing oxidative stress, neuronal death, and severe cognitive impairment. Modulation of Aβ42 aggregation via various structurally anisotropic macromolecular systems is considered effective in protecting neuronal cells. In this regard, we have developed a cyclic dipeptide (CDP)-based copolymer (CP) and explored its material and biomedical properties. Owing to the structural versatility, CDP-CP forms solvent-dependent anisotropic architectures ranging from dense fibers and mesosheets to vesicles, which are shown to interact with dyes and nanoparticles and mimic synthetic protocells, providing a conceptually new approach to achieve advanced functional materials with the hierarchical organization. CP upon interaction with gold nanoparticles (GNP) and polyoxometalate (POM) generated faceted architectures (CP-GNP) and the nanocomposite (CP-POM), respectively. CP-GNP and CP-POM have shown remarkable ability to inhibit Aβ42 aggregation, dissolve the preformed aggregates, and scavenge reactive oxygen species (ROS) to ameliorate multifaceted amyloid toxicity. In cellulo studies show that CP-GNP and CP-POM protect neuronal cells from Aβ42-induced toxicity and reduce lipopolysaccharide (LPS)-activated neuroinflammation at sub-micromolar concentration. To our knowledge, this is the first report on the hierarchical organization of CDP-CP into 1D-to-2D architectures and their organic–inorganic hybrid nanocomposites to combat the multifaceted amyloid toxicity