Acta Pharmaceutica Sinica B

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Probiotic living microneedles designed by interbacterial competition for accelerated infected wound healing

Acta Pharmaceutica Sinica B. 2025, 15(12): 6571-6586.

Probiotic therapy offers a promising strategy for chronic infected wound management through pathogen suppression and immune modulation. However, its efficacy remains restricted by weak competitiveness in pathogen-rich niches and poor penetration across biofilm barriers. Inspired by bacterial competitive interactions, we developed a multifunctional microneedle (MN) platform to overcome these limitations. Lactobacillus reuteri (Lr) was coated with poly-l-lysine-modified metal–phenolic networks (MPNs) encapsulating doxorubicin (DOX), yielding DOX@MPN–PLL@Lr (DMP@Lr). The engineered probiotics were incorporated into dissolving MNs enriched with nutrient broth to ensure excellent microneedle performance and probiotic function. This design leverages MPN multifunctionality to reduce early-stage pathogenic burden via photothermal-assisted bacterial killing and near-infrared (NIR)-promoted antibiotic release, thereby enhancing probiotic competitiveness. Meanwhile, MNs physically disrupt biofilms for precise delivery into deep infection sites. In vitro, DMP@Lr achieved >99.9% (5.5 log) bactericidal efficiency, and its MNs exhibited a 1.4-fold higher biofilm clearance compared with blank MNs. In vivo, a single DMP@Lr MN patch promoted 93.9% wound closure, demonstrating potent antibacterial activity and accelerated healing. This study presents an innovative, translatable probiotic-based MN therapy for the effective treatment of chronically infected wounds.
Butyrylated Smilax glabra starch relieves atopic dermatitis through gut-skin axis modulation via colon-targeted delivery

Acta Pharmaceutica Sinica B. 2025, 15(12): 6587-6606.

Atopic dermatitis (AD) is a prevalent cutaneous condition with chronic inflammation and immune dysregulation, posing a public health concern owing to its long-lasting and recurrent nature. Butyrate, a short-chain fatty acid produced by gut microbiota, exhibits significant anti-inflammatory effects in AD. Yet, its delivery via butyrylated starch for prolonged release in the colon has not been adequately investigated. In this study, butyrylated Smilax glabra starch (BSGS) was synthesized and its therapeutic potential against AD via modulation of the gut–skin axis was examined. BSGS exhibited a C-type crystalline structure and highly resistance to gastrointestinal digestion. In vitro anaerobic fermentation showed that BSGS effectively promoted the generation of short-chain fatty acids, especially butyrate, and positively influenced the gut microbial composition. In AD mice, BSGS administration considerably mitigated cutaneous inflammation, lowered serum proinflammatory cytokines, restored intestinal barrier integrity, and modulated gut microbiota by increasing Bacteroides and norank_f__Prevotellaceae while decreasing Alistipes and norank_o__RF39. This therapeutic effect was associated with butyrate release and NF-κB pathway suppression, as evidenced by the reduced phosphorylation of p65 and IκBα. These findings establish that BSGS, a novel colon-targeted butyrate donor, holds promising potential in AD treatment by modulating the immune system via the gut–skin axis.
Targeting renal tubular epithelial cells via a dual functionalized oligosaccharide self-assembly in the management of acute and chronic kidney diseases

Acta Pharmaceutica Sinica B. 2025, 15(12): 6607-6625.

The kidneys are susceptible to hypoxia, proteinuria, and toxins, which can trigger acute kidney injury (AKI). Maladaptive repair of AKI results in the development of chronic kidney disease (CKD). Epithelial-mesenchymal transition (EMT) represents a pivotal mechanism underlying renal interstitial fibrosis (RIF). Myofibroblasts represent the primary effector cells of RIF with over 30% derived from renal tubular epithelial cells (RTECs). RTECs play a crucial role in CKD by generating part of EMT, while Snail1 is an effective inducer of EMT. Therefore, silencing Snail1 in RTECs and blocking the EMT process represents an original approach for treating RIF. Here, the positively charged l-arginine (L-Arg) and the hydrophobic fragment stearic acid (SA) were introduced on the chitosan oligosaccharide to afford a dual-targeted COA-SA micelle via size-, charge- and active targeting effects. The micelle overcomes the substantial disparity in physical and chemical properties between hydrophilic nucleic acid macromolecules and the anti-inflammatory small molecule celastrol and successfully establishes a codelivery platform. In vivo, COA-SA micelles can traverse the blood circulation, and glomerular filter, and overcome intracellular barriers to achieve efficient and precise drug delivery to RTECs. This results in the successful reversal of the EMT process in RTECs, thereby achieving a favorable anti-fibrosis effect.
Hemoglobin nanocatalyst with tunable autoxidation activity for tumor apoptosis-ferroptosis combination therapy

Acta Pharmaceutica Sinica B. 2025, 15(12): 6626-6637.

The clinical translation of catalytic therapy has been hindered in recent decades due to immunological risks, delayed degradation, and poorly understood metabolism associated with catalysts, despite promising results in antitumor therapy. Developing catalysts with nonmetallic active centers may provide an alternative to those with metallic active centers. In this study, a natural protein nanocatalyst, Hb@PtPP, is developed through the moderate polymerization of pyrrole and hemoglobin for tumor catalytic therapy. In comparison with BSA@PtPP prepared from bovine serum albumin, Hb@PtPP exhibits distinctive autoxidation activity in tumor cells in response to elevated hydrogen peroxide levels while maintaining relatively low activity in normal cells. This feature enables Hb@PtPP to effectively combat tumors by initiating a cascade of catalytic reactions, including the production of reactive oxygen species, the release of heme and iron ions, and the accumulation of lipid peroxidation, all of which contribute to apoptosis and ferroptosis in tumor cells. RNA-sequencing results further demonstrate that tumor cells undergo ferroptosis. Additionally, these catalytic processes are augmented by the photothermal effect, resulting in efficient tumor killing and growth inhibition both in vitro and in vivo. This study underscores the crucial role of hemoglobin in advancing catalytic therapy for tumors.
Injectable hydrogel-mediated co-delivery of oncolytic adenovirus and melphalan for retinoblastoma control and vision preservation

Acta Pharmaceutica Sinica B. 2025, 15(12): 6638-6656.

Retinoblastoma (RB) is the most common primary ocular malignancy in children, arising from the developing retina. While higher doses of local chemotherapy have improved tumor control, concerns regarding retinal toxicity and the development of chemoresistance remain significant. Oncolytic adenovirus (OA) presents a promising therapeutic approach for RB, but rapid clearance often limits its therapeutic effects. In this study, we engineered a genetically modified OA derived from human adenovirus 5 (Ad5), designed to selectively target and lyse RB cells. The combination of OA with low-dose melphalan demonstrates an enhanced antitumor effect, while minimizing retinal toxicity. In vitro and in vivo experiments demonstrated that melphalan significantly enhanced the antitumor effect of OA and extended ocular survival. More importantly, we developed a biocompatible injectable hydrogel delivery system based on the covalent coupling of collagen and aldehyde-modified cyclodextrin, which effectively enhances the loading efficiency of melphalan and enables sustained co-delivery of OA and melphalan. The mouse RB tumor model confirmed that this hydrogel system (OA-Mel@CCA) achieved localized and sustained delivery of both therapeutics, effectively controlling tumor growth and preventing brain metastasis. Additionally, retinal structure and function were notably preserved in mice treated with OA-Mel@CCA, with no observed retinal toxicity. These findings suggest that the injectable hydrogel-based co-delivery of melphalan and oncolytic adenovirus could represent a promising strategy for RB treatment.
LSD1 inhibition sensitizes anti-PD1 blockade immunotherapy by inhibiting the long-range attack of tumor-derived extracellular vesicles

Acta Pharmaceutica Sinica B. 2025, 15(12): 6657-6680.

Programmed cell death protein-1/programmed cell death ligand-1 (PD1/PD-L1) blockade has shown promise in cancer therapy but remains limited by low response rates. Recent efforts have explored strategies to enhance immunotherapy efficacy. Histone lysine-specific demethylase 1 (LSD1) inhibition can enhance tumor immune responses by downregulating PD-L1 expression. Furthermore, PD-L1 in tumor cell-derived extracellular vesicles (EVs) contributes to the immunosuppressive tumor microenvironment (TME) and promotes immune evasion. Here, we found that LSD1 inhibition can mediate the rearrangement of PD-L1 on tumor cell surfaces, reduce the secretion of EVs and PD-L1 levels in the TME, and ultimately block the long-range immunosuppression caused by tumor cell-released EVs. Therefore, we developed a TME-targeted synergistic therapy system with a dual mechanism in which anti-PD1 therapy blocks immune checkpoints, and forsythiaside A (FA) acts as an LSD1 inhibitor to regulate EVs secretion. Additionally, CD4⁺ T cells can directly kill tumor cells by inducing G1/S cell cycle arrest. Ultimately, this system activates the tumor immune response within the TME, effectively inhibiting the growth of non-small cell lung cancer tumors. Our work highlights the signaling role of EVs and the capacity of CD4⁺ T cells to arrest the cell cycle, offering a new approach to enhance response to anti-PD1/PD-L1 therapy.
RDYH58 functional exosomes targeting myofibroblasts loaded with siFKBP10 for inhibition of collagen biosynthesis and secretion of IPF

Acta Pharmaceutica Sinica B. 2025, 15(12): 6681-6697.

Idiopathic pulmonary fibrosis (IPF) is a complex interstitial lung disease in which myofibroblasts are the primary effector cells. FK506-binding protein (FKBP10), a procollagen chaperone, is upregulated in IPF and primarily localizes to myofibroblasts. Exosomes have garnered significant attention as novel drug delivery vehicles, particularly when engineered. However, myofibroblasts remain underexplored in terms of engineered exosome-based therapies and associated drug targets. In this study, RDYH58, a peptide that targets myofibroblasts, was conjugated to the exosomal membrane protein Lamp2b to produce RDYH58-linked exosomes (RDYH58-exo). In vitro and in vivo experiments demonstrated that compared to unmodified exosomes (unm-exo), RDYH58-exo preferentially localized to myofibroblasts. A small interfering RNA targeting FKBP10 (siFKBP10) was loaded into exosomes using ultrasonic microfluidics method, and the antifibrotic effects of RDYH58-exo carrying siFKBP10 (RDYH58-siFKBP10) were assessed both in vitro and in vivo. The results demonstrated that RDYH58-siFKBP10 effectively silenced FKBP10 gene expression, significantly inhibiting fibroblast activation and extracellular matrix deposition, with superior antifibrotic efficacy compared to unmodified exosome vectors (unm-siFKBP10). RNA-seq analysis confirmed the pivotal regulatory role of FKBP10, providing critical evidence for the development of targeted therapeutic strategies. The RDYH58-siFKBP10 delivery system developed in this study demonstrates remarkable clinical translation potential.
Standardization of nasal airway structure model of Chinese Han nationality for characterization of nasal formulation spatial deposition atlases

Acta Pharmaceutica Sinica B. 2025, 15(12): 6698-6713.

The deposition characteristics of nasal formulations directly determine the efficacy of the drugs, whilst the complexity of human nasal airway structure encumbers quantitative evaluation of nasal spatial deposition. Male and female standard nasal airway structure models were calculated from computed tomography data of 128 Chinese Han nationality using statistical shape model. The deposition evaluation devices were further designed, and an imaging method was then employed to obtain drug deposition information. Furthermore, drug spatial deposition atlases were proposed by UV unwrapping, a mathematical mapping procedure flattening three-dimensional (3D) information to two-dimension bidirectionally, to achieve quantification of drug deposition fractions in the regions of interest. Moreover, the feasibility and universality of this method were verified by correlating it with the chemical quantitative results and computational fluid dynamic simulation of drug deposition of mometasone furoate nasal spray and hydroxypropyl methylcellulose nasal powder, respectively. Finally, the unique drug spatial deposition atlases of these two formulations in the male and female evaluation devices were generated, respectively. In summary, the standard nasal airway structure models of the Chinese Han nationality and the drug spatial deposition atlases provide scientific tools for the formulation optimization and quality control of nasal formulations.
Development of a novel ¹⁸F-labeled reversible-binding radioligand for imaging monoacylglycerol lipase with positron emission tomography

Acta Pharmaceutica Sinica B. 2025, 15(12): 6714-6726.

Monoacylglycerol lipase (MAGL) constitutes a crucial serine hydrolase within the endocannabinoid system, which has been suggested as a potential therapeutic target for the treatment of various neurodegenerative disorders. While MAGL inhibitors have entered the clinical arena, a highly selective and MAGL-specific positron emission tomography (PET) ligand holds promise to significantly facilitate clinical drug development by allowing the quantification of MAGL levels and the assessment of target occupancy in patients. Accordingly, this study aimed to develop a new series of reversible MAGL inhibitor candidates, based on a piperazinyl azetidine diamide scaffold. Compound 3 demonstrated the most promising performance characteristics in pharmacological evaluations compared to other MAGL inhibitor candidates. Subsequently, it was labeled with fluorine-18 and further assessed through autoradiography and PET imaging, as well as ex vivo biodistribution and metabolite analysis experiments in rodents. Compound 3 exhibited a heterogeneous radioactivity distribution, favorable brain uptake, and excellent in vivo binding specificity. Target occupancy studies with a therapeutic MAGL inhibitor demonstrated a dose-dependent PET signal reduction of [¹⁸F]3 in rat brains. In conclusion, [¹⁸F]3 ([¹⁸F]MAGL-2011) has the potential to serve as an effective MAGL PET ligand.
Preclinical characterization and anti-RSV efficacy of an oral C-nucleoside derivative

Acta Pharmaceutica Sinica B. 2025, 15(12): 6727-6730.

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