Biologics represent a major advance in therapy, offering highly specific and potent treatment options for diseases previously difficult to manage; however, their administration routes are commonly limited to injection due to poor oral bioavailability, which can lead to patient inconvenience and adherence challenges. The pulmonary route offers a promising alternative, leveraging the lung’s large absorptive surface area, thin alveolar-capillary barrier, rich vascularization, and avoidance of first-pass metabolism to enable both local and systemic delivery. Effective inhaled biologic therapies require harmonizing the drug’s physicochemical properties with aerosol aerodynamic behavior and dissolution. The pharmacokinetic fate of inhaled biologics is further influenced by lung physiology, including airflow dynamics, airway structure, mucociliary clearance, and respiratory lining fluid composition. These factors present significant barriers to the stability, absorption, and retention of inhaled biologics. Extensive research efforts focus on optimizing formulations, inhalation devices, and excipients, alongside deepening the understanding of the biopharmaceutical characteristics of inhaled biologics. This review summarizes recent advances in inhalation systems of therapeutic peptides and proteins for systemic and local effects, emphasizing practical strategies to overcome key biopharmaceutical and physicochemical challenges, thus advancing the clinical potential of next-generation inhaled biologics.

Through the heterologous expression of a highly reducing polyketide synthase and a thioesterase from the apeml cluster, a putative macrolide biosynthetic gene cluster on the genome of Aspergillus petrakii, we obtained a naturally new 10-membered macrolide (1) and recifeiolide (2), a known 12-membered macrolide. To obtain modified macrolides, feeding experiments using Aspergillus oryzae transformants expressing individual modification enzymes were employed, resulting in the isolation of aspinolide A (3) and 2 new macrolides, petrakilides A (4) and B (5). These findings highlight a promiscuous enzymatic cascade capable of generating macrolides with distinct scaffolds and different ring sizes.

Dendrobium Sw. is one of the largest genera in the Orchidaceae. Most species belong to one of two major clades (the Asian and the Australasian clades) based on morphology and phylogenetic analyses using DNA sequences. Several Dendrobium species in the Asian clade are used in traditional herbal medicine, and many compounds have been isolated from them (e.g., phenanthrene derivatives, bibenzyl derivatives, and polysaccharides). Conversely, there are only a few reports on the compounds contained in the Australasian clade species. Due to its size and diversity, the Australasian clade could be expected to contain compounds of potential medicinal value as well. Previously, we constructed the HPLC profile of 18 Dendrobium species and identified the phenanthrene derivative 1,5-dimethoxyphenanthrene-2,7-diol (1) as a characteristic compound in certain species of the Australasian clade. In this study, we performed metabolic analyses based on ¹H-NMR to identify lineage-correlated metabolites for the Australasian clade. NMR profiling analysis also showed that 1 is a characteristic compound of the Australasian clade species. Additionally, pinoresinol (2) was predominantly detected in the Australasian clade. While syringaresinol (3) was widely detected in species from both clades, specimens from the Australasian clade tended to have higher concentrations. The simple ¹H-NMR profiling method enables rapid comparison of metabolites across multiple species, providing new insights into metabolic differences associated with evolutionary lineages that were not detectable by the previous HPLC profiling.

Twelve side-chain fluorinated 2α-[2-(tetrazol-2-yl)ethyl]-1α,25-dihydroxyvitamin D₃ (AH-1) analogs were designed, synthesized, and evaluated regarding their biological activities. Synthesis was carried out employing the palladium-catalyzed Trost coupling reaction between side-chain fluorinated CD-ring bromo-olefins 41–52 and A-ring enyne 53. Some analogs, including C26,27-hexafluoro-AH-1 (31) and 24,24-difluoro-AH-1 (34), exhibited much higher human vitamin D receptor binding affinity, VDR-ligand binding domain transcriptional activity, osteocalcin promoter transactivation activity, and metabolic resistance to CYP24A1-mediated inactivation than 1α,25(OH)₂D₃.

Herein, we report the catalytic asymmetric intramolecular dearomative coupling of tethered phenols in ortho-para fashion under aerobic conditions. Cooperative catalysis with a chromium-salen complex/nitroxyl radical enabled the desired transformation to proceed at ambient temperature under oxygen atmosphere. A range of tethered phenols were efficiently converted into spirocyclic 2,4-dienones in moderate to good yields and enantioselectivities (up to 68% enantiomeric excess (ee)).