Investigation of Factors Influencing the Effectiveness of Deformable Nanovesicles for Insulin Nebulization Inhalation.

Nebulized inhalation offers a noninvasive method for delivering drugs to treat both local respiratory and systemic diseases. In this study, insulin was used as a model drug to design a series of deformable nanovesicles (DNVs) with key quality attributes, including particle size, deformability, and drug load capacity. We investigated the effects of these properties on aerosol generation, macrophage phagocytosis, and bloodstream penetration. The results showed that deformability improved nebulization performance and reduced macrophage phagocytosis, benefiting local and systemic delivery. However, the advantage of DNVs for transmembrane penetration was not evident in the alveolar epithelium. Within the size range of 80-490 nm, the smaller the particle size of IPC-DNVs, the easier it is to evade clearance by macrophages and the more effective the in vivo hypoglycemic efficacy will be. In the drug load range of 3-5 mg/mL, a lower drug load resulted in better hypoglycemic efficacy. The area above the blood glucose decline curve with time (AAC) of nebulized DNVs was 2.32 times higher than that of the insulin solution, demonstrating the feasibility and advantages of DNVs in the pulmonary delivery of biomacromolecule drugs. This study provides insights into the construction and formulation optimization of pulmonary delivery carriers.

Unlocking the potential of amorphous calcium carbonate: A star ascending in the realm of biomedical application.

Calcium-based biomaterials have been intensively studied in the field of drug delivery owing to their excellent biocompatibility and biodegradability. Calcium-based materials can also deliver contrast agents, which can enhance real-time imaging and exert a Ca2+-interfering therapeutic effect. Based on these characteristics, amorphous calcium carbonate (ACC), as a brunch of calcium-based biomaterials, has the potential to become a widely used biomaterial. Highly functional ACC can be either discovered in natural organisms or obtained by chemical synthesis However, the standalone presence of ACC is unstable in vivo. Additives are required to be used as stabilizers or core-shell structures formed by permeable layers or lipids with modified molecules constructed to maintain the stability of ACC until the ACC carrier reaches its destination. ACC has high chemical instability and can produce biocompatible products when exposed to an acidic condition in vivo, such as Ca2+ with an immune-regulating ability and CO2 with an imaging-enhancing ability. Owing to these characteristics, ACC has been studied for self-sacrificing templates of carrier construction, targeted delivery of oncology drugs, immunomodulation, tumor imaging, tissue engineering, and calcium supplementation. Emphasis in this paper has been placed on the origin, structural features, and multiple applications of ACC. Meanwhile, ACC faces many challenges in clinical translation, and long-term basic research is required to overcome these challenges. We hope that this study will contribute to future innovative research on ACC.

Herpesvirus-Mimicking DNAzyme-Loaded Nanoparticles as a Mitochondrial DNA Stress Inducer to Activate Innate Immunity for Tumor Therapy.

Virus-based immunotherapy is a promising approach to treat tumor. Closely mimicking the structure and sequential infection processes of natural viruses is highly desirable for effective tumor immunotherapy but remains challenging. Here, inspired by the robust innate immunity induced by herpesvirus, a herpesvirus-mimicking nanoparticle (named Vir-ZM@TD) is engineered for tumor therapy by mimicking the structure and infection processes of herpesvirus. In this biomimetic system, DNAzyme-loaded manganese-doped zeolitic imidazolate framework-90 (ZIF-90) nanoparticles (ZM@TD) mimic the virus nucleocapsid containing the genome; the erythrocyte membrane mimics the viral envelope; and two functional peptides, RGD and HA2 peptides, resemble the surface glycoprotein spikes of herpesvirus. Vir-ZM@TD can both effectively evade rapid clearance in the blood circulation and closely mimic the serial infection processes of herpesvirus, including specific tumor targeting, membrane fusion-mediated endosomal escape, and TFAM (transcription factor A, mitochondrial) deficiency-triggered mitochondrial DNA stress, as well as the release of manganese ions (Mn2+ ) from organelles into the cytosol, ultimately effectively priming cGAS-STING pathway-mediated innate immunity with 68% complete regression of primary tumors and extending by 32 days the median survival time of 4T1-tumor-bearing mice.

Bionic Regulators Break the Ecological Niche of Pathogenic Bacteria for Modulating Dysregulated Microbiome in Colitis.

Therapeutic approaches that reprogram the gut microbiome are promising strategies to alleviate and cure inflammatory bowel disease (IBD). However, abnormal expansion of Escherichia coli during inflammation can promote pathogenic bacteria occupying ecological niches to resist reprogramming of the microbiome. Herein, a bionic regulator (CaWO4 @YCW) is developed to efficiently and precisely regulate the gut microbiome by specifically suppressing the abnormal expansion of E. coli during colitis and boosting probiotic growth. Inspired by the binding of E. coli strains to the mannose-rich yeast cell wall (YCW), YCW is chosen as the bionic shell to encapsulate CaWO4 . It is demonstrated that the YCW shell endows CaWO4 with superior resistance to the harsh environment of the gastrointestinal tract and adheres to the abnormally expanded E. coli in colitis, specifically as a positioner. Notably, the high expression of calprotectin at the colitis site triggers the release of tungsten ions through calcium deprivation in CaWO4 , thus inhibiting E. coli growth by replacing molybdenum in the molybdopterin cofactor. Moreover, YCW functions as a prebiotic and promotes probiotic growth. Consequently, CaWO4 @YCW can efficiently and precisely reprogram the gut microbiome by eliminating pathogenic bacteria and providing prebiotics, resulting in an extraordinary therapeutic advantage for DSS-induced colitis.