Oral delivery of therapeutic peptides has been a daunting challenge due to poor transport across the tight junctions and susceptibility to enzymatic degradation in the gastrointestinal tract. Numerous advancement in nanomedicine has been made for the effective delivery of protein and peptide. Owing to the superior performance of chitosan in opening intercellular tight junctions of epithelium and excellent mucoadhesive properties, chitosan-based nanocarriers have recently garnered considerable attention, which was formulated in this paper to orally deliver the GLP-1 drug (Exenatide). Against this backdrop, we used chitosan (CS) polymers to encapsulate the exenatide, sodium tripolyphosphate (TPP) as the cross-linking agent and coated the exterior with sodium alginate (ALG) to impart the stability in an acidic environment. The chitosan/alginate nanoparticles (CS-TPP-ALG) functioned as a protective exenatide carrier, realized efficient cellular uptake and controlled release, leading to a steady hypoglycemic effect and a good oral bioavailability in vivo. Trimethyl chitosan (TMC), a chitosan derivative with stronger positive electrical properties was additionally selected as a substitute for chitosan to construct the TMC-TPP-ALG nanoparticle, and its oral peptide delivery capacity was explored in terms of both characterization and pharmacodynamics studies. Overall, our study demonstrated that functional chitosan/alginate nanoparticles can protect proteins from enzymatic degradation and enhance oral absorption, which presents important research value and application prospects.

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Acute inflammatory visceral pain (AIVP) is a prevalent yet challenging clinical condition associated with inflammatory diseases, characterized by diffuse pain that often escalates into nausea, vomiting, and systemic autonomic disturbances. The absence of effective and patient-centered therapies remains a significant clinical challenge. While dexmedetomidine (Dex) has demonstrated promising analgesic effects, its conventional intravenous administration involves slow infusion, heightening risks of infection and compromising patient comfort and compliance. Here, we present a breakthrough strategy using a hyaluronic acid (HA) hydrogel and microneedle-based transdermal system for Dex delivery to enhance clinical practicality. We successfully fabricated Dex-loaded HA hydrogel microneedles (MN/Dex), enabling efficient skin penetration and controlled drug release. Comprehensive biosafety evaluations, including skin irritation, cytotoxicity, and hemolysis assays, confirmed the excellent biocompatibility of the HA hydrogel microneedle system (HA-MN). In the acetic-acid-induced AIVP model, MN/Dex not only produced significant and sustained reduction in visceral and somatic hyperalgesia but also maintained normal physiological activity, avoiding sedation burden, preserving feeding behavior, and supporting natural mobility. MN/Dex offers a minimally invasive, easy-to-administer, and well-tolerated alternative to intravenous therapy, with the potential to transform outpatient management and improve quality of life for patients suffering from AIVP. This advanced delivery platform bridges a critical translational gap in pain management, combining efficacy with outstanding clinical adaptability.

Background: Local drug delivery can increase antitumor exposure while limiting systemic toxicity, but chemotherapy-only local treatment may not fully control residual tumor growth in immunosuppressive tumor microenvironments. This study aimed to develop and preliminarily evaluate ffky-antiCD3, a CD3-recognition peptide-functionalized self-assembling peptide platform for intratumoral doxorubicin (DOX) delivery. Methods: The Nap aromatic group in a previous Nap-ffky scaffold was removed to improve aqueous dispersibility, and the CD3-recognition sequence AKMGEGGWGANDY was introduced to generate ffky-antiCD3. The peptide/formulation was characterized by reversed-phase high-performance liquid chromatography, mass spectrometry, TEM, circular dichroism spectroscopy, and a preliminary in vitro DOX release assay under tumor-mimicking acidic conditions. Antitumor efficacy, tumor histopathology, image-based CD3/CD8 semi-quantification, splenic IFN-γ levels, serum biochemistry, organ coefficients, and major-organ histology were assessed after repeated intratumoral treatment in B16-F10 melanoma-bearing C57BL/6 mice. Results: ffky-antiCD3 formed assemblies with a β-sheet-rich secondary structure. TEM observation further showed heterogeneous irregular/network-like supramolecular assemblies, and the preliminary release assay suggested slower apparent DOX release from ffky-antiCD3/DOX than from free DOX at pH 6.5. Among the tested groups, ffky-antiCD3/DOX produced the strongest short-term tumor-growth inhibition and the lowest endpoint tumor weight during the 10-day observation period. Ki67 staining decreased, and TUNEL signals increased after ffky-antiCD3/DOX treatment, supporting reduced proliferation and enhanced apoptosis-related damage. CD3/CD8 staining and exploratory splenic IFN-γ measurements indicated preliminary immune-related changes associated with ffky-antiCD3-containing formulations. Body weight, organ weights, serum biochemical markers, and major-organ H&E staining revealed no obvious short-term toxicity signals under the tested regimen. Conclusions: ffky-antiCD3/DOX represents a candidate local peptide-based chemo-immunomodulatory formulation. Its immune mechanism, release behavior, biodistribution, and long-term efficacy and safety require further validation before strong mechanistic or translational claims are made.