Xiaohui Yan

Anthraquinone-fused enediynes (AFEs) are a class of microbial natural products with remarkable cytotoxicity and exhibit promising application prospects in tumor therapy. Taking tiancimycins (TNMs) as an example, this class of compounds holds great potential against triple-negative breast and liver cancers. However, the low production titers of AFEs in actinobacterial hosts make their enrichment and separation processes both cumbersome and costly. Therefore, the main objective of this study was to develop a rapid and reusable magnetic platform for TNM enrichment and recovery. Inspired by the pi-pi stacking interactions between AFEs and their natural binding proteins in the producing strains, this study designed and prepared alizarin- and folic acid-co-modified magnetic nanoparticles (PNMP-AZ-FA). On the one hand, these nanoparticles can directly and specifically adsorb TNMs from the crude extract of Streptomyces sp. CB03234-S, enabling efficient separation. On the other hand, the folic acid modification was explored as a proof-of-concept delivery element for drug-loaded nanoparticles in folate receptor (FR)-expressing tumor models. PNMP-AZ-FA showed loading capacities of 87.8 and 106.7 mg/g for TNM A and TNM D, respectively, and retained high adsorption performance during 20 repeated cycles. Animal experiment results demonstrated that the TNM-loaded nanoparticle (PNMP-AZ-FA@TNM A) improved antitumor activity under the tested conditions, especially in the FR-high KB model; however, receptor-dependent uptake, biodistribution, and pharmacokinetic validation are still required. In summary, this nanoparticle holds great application prospects in the rapid separation and acquisition of AFEs, while its tumor-delivery application should be regarded as preliminary evidence.

Chiral amino-indanes are valuable pharmaceutical intermediates, yet their efficient asymmetric synthesis remains challenging. In this study, enzymatic reduction of imines using enantiocomplementary IREDs enabled the synthesis of chiral amino-indanes. Furthermore, a one-pot, two-step cascade reaction combining trimethyl borate-promoted imine formation with IRED-catalyzed imine reduction was established to produce chiral amino-indanes with 87–99% ee values via a continuous fed-batch strategy, providing environmentally friendly and economical access to these pharmaceutically relevant compounds.

The synthesis of non-canonical amino acids (ncAAs) has recently made tremendous progress in the field of biocatalysis, with enzymes such as transaminases, dehydrogenases, and ammonia lyases being used. Frameworks of β-branched aromatic D-amino acids are crucial for the efficacy of pharmaceuticals, influencing spatial conformation, binding modes with receptors and pharmacokinetic properties. However, there is a scarcity of studies on the efficient synthesis of β-branched D-amino acids, which has significantly hindered the advancement of structure-activity relationship (SAR) studies. Here, we present the asymmetric synthesis of β-branched aromatic D-amino acid analogues catalyzed by PLP-dependent transaminase BsDAAT (from Bacillus sp. strain YM-1), an efficient transamination system that relies on the dynamic kinetic resolution (DKR) process. Through docking analysis and concise enzyme engineering, we successfully obtain various aromatic D-amino acids with β-substitution in high yields (up to 99%), dr ratios (>20:1) and ee values (up to 99%). These β-branched aromatic D-amino acids are then successfully introduced into the modifications of the antineoplastic reagent Lanreotide.

β-Carotene has extensive applications in the food, pharmaceutical, and cosmetics industries. Traditional chemical synthesis methods face challenges such as byproduct residues and high costs, whereas natural extraction is constrained by low yields and complex processes. Recent advancements in synthetic biology and metabolic engineering have paved the way for the heterologous biosynthesis of β-carotene in microorganisms. Owing to its rapid growth, convenience of genetic manipulation, and suitability for producing apocarotenoids, Escherichia coli is an ideal host for the production of β-carotene and its derivatives, as exemplified by the record production of multiple apocarotenoids in engineered E. coli strains. Here, we summarize the metabolic engineering strategies employed to produce β-carotene in E. coli, including manipulation of the endogenous MEP pathway, introduction of the hybrid MVA pathway, modulation of central carbon metabolism, modification of the cell membrane, and fermentation process optimization. As β-carotene acts as a biosynthetic hub for many carotenoids and apocarotenoids, we also highlighted the importance of efficient β-carotene production for the sustainable preparation of these compounds. This review aims to provide theoretical insights for designing talented β-carotene producers and laying the foundation for the sustainable manufacturing of valuable carotenoids and apocarotenoids.

The structure and arrangement of the micropillar array in the micropillar capillary pump have a significant influence on its flow resistance and flow rate. Therefore, research and prediction of the conveying performance can provide valuable guidance for the design of the capillary pump. In this study, we designed a high-flux capillary pump using large-sized micropillars. The flow rate and resistance of the pump were investigated through numerical simulations under various arrangement patterns, with a fixed column height of 0.4 mm and minor axis lengths ranging from 0.1 to 0.75 mm. It is found that the performance of the capillary pump is different when the shape or arrangement of the micropillars is changed. Considering the resistance and flow rate, the pumping effect of rhomboid micropillars is the best. Compared with the capillary pump with low height and small-sized capillary columns, the flow resistance of the pump is small, and the flux can be increased by dozens of times, but the side friction resistance and front form drag between the fluid and the micropillars cannot be ignored. In this study, the dynamic formula considering the side friction resistance is derived, and the resistance prediction formula of the high-flux capillary pump is derived according to the simulation results.

Terpenoids are the most structurally diverse class of natural products (NPs). Despite their abundance, the functional diversity of bacterial terpene synthases (TPSs), particularly from Streptomyces species, remains largely unexplored. In this study, fourteen Streptomyces strains were subjected to genome sequencing and bioinformatic analysis to systematically mine class I TPSs. A total of forty-eight TPSs were identified and categorized through phylogenetic analysis, and five representative TPSs distantly related to known TPSs were selected for functional investigation. Biochemical assays revealed that TAC28_6116 is a sesquiterpene synthase producing thujopsan-2β-ol (1) and thujopsene (2), marking the first report of thujopsan-2β-ol production from a bacterial source. TAC49_7078 is a diterpene synthase responsible for the formation of ent-phomacta-1(15),3,7-triene (3). Notably, TAC43_2999 was identified as a novel sesterterpene synthase that produced compound 5 in vitro, while the generation of a previously undescribed compound 6, sestermalaysiene, was exclusively detected during in vivo fermentation using the engineered Escherichia coli chassis optimized for terpenoid biosynthesis. Structural elucidation of sestermalaysiene was supported by nuclear magnetic resonance (NMR) analysis and quantum chemical calculations. Its formation might proceed via a rare [4 + 2] cycloaddition mechanism. Overall, this work expands our knowledge of the catalytic diversity of bacterial TPSs and offers promising biocatalysts for terpenoid engineering and discovery.

Activation of the STING pathway is essential for restoring immune surveillance against dormant disseminated tumor cells (DTCs) in the lungs. Inhaled Mn²⁺ has potential as a STING agonist; however, its clinical application is limited by the risk of chronic inflammation and metastasis, primarily due to reactive oxygen species (ROS) generation during inhalation. To address these risks, salvianolic acid B (salB) was identified as an effective ionophore for Mn²⁺, enhancing STING activation while mitigating ROS-induced inflammation. In this study, salB mitigated Mn²⁺-induced ROS levels and enhanced STING signaling, providing a safer, noninflammatory approach to activating immune surveillance in lung DTCs. The salB-Mn²⁺ complexes were encapsulated in human serum albumin nanoparticles (HSA NPs) for inhalation. PET and MRI analyses revealed that intratracheal administration of HSA NP@salB-Mn²⁺ restricted Mn²⁺'s systemic distribution, retaining it primarily in the lungs and minimizing central nervous system accumulation. Subsequent lung immunofluorescence further confirmed that HSA NP@salB-Mn²⁺ effectively targeted lung metastatic lesions. Despite this extended retention in lung tissue, histological analysis showed minimal inflammation in mice treated with HSA NP@salB-Mn²⁺, in contrast to those receiving MnCl₂ or MnO. Consequently, HSA NP@salB-Mn²⁺ demonstrated superior suppression of 4T1 cell lung metastasis in postsurgical mice relative to MnCl₂ or MnO. Mechanistically, salB functions as an agonist, independently activating p-STING, which synergizes with Mn²⁺-induced STING activation to significantly amplify signaling and downstream target engagement. In a postsurgical mouse model, the combination of HSA NP@salB-Mn²⁺ and αPD-1 antibody significantly reduced DTC dormancy and enhanced immune detection, confirming its immunotherapeutic potential. These findings establish salB as a promising inhalable ionophore for Mn²⁺ in DTC treatment, providing three key advantages: prolonged lung retention, reduced inflammation risk, and enhanced STING-activating efficacy.