Acta Pharmaceutica Sinica B

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Exploring the therapeutic potential of cannabidiol in soft tissue wound healing: Delivery strategies and anti-inflammatory pathways

Acta Pharmaceutica Sinica B. 2026, 16(4): 2174-2195.

This review explores the molecular and cellular pathways of soft tissue wound healing and the potential therapeutic use of the non-psychotropic cannabinoid cannabidiol (CBD), integrating findings from in vitro and in vivo preclinical studies as well as completed and ongoing clinical trials. It provides a comprehensive summary of the next steps in new CBD-based product development by analyzing current trends in dosage optimization, treatment guidance, delivery systems, ranging from liposomes, microemulsions to hydrogels. Additionally, the review examines clinical trials related to CBD formulations, delivery routes, and participant outcomes, offering a deeper understanding of the mechanisms guiding the activity beyond binding to cannabinoid 1 (CB1) and CB2 receptors. Furthermore, it highlights challenges and future perspectives in CBD formulation studies, presenting both currently studied approaches and emerging possibilities for innovation. Therapeutic potential of CBD has proved itself in the recent years and only regulatory issues and clarity in treatment and delivery routes will limit its widespread use in soft tissue healing.
Self-assembled nanoplatforms for cancer immunotherapy: Principles, progress and perspectives

Wenfei Xu, Shuxuan Zhu, Zhaogang Sun, Jun Ye, Hongqian Chu

Acta Pharmaceutica Sinica B. 2026, 16(4): 2196-2231.

Cancer immunotherapy is an innovative treatment approach that leverages the immune system's ability to identify and attack tumor cells. Its goal is to initiate or re-establish the tumor-immune cycle. However, challenges such as limited response rates and adverse immune responses have hindered the further application and advancement of this therapy. Recent progress in nanomedicine, particularly in self-assembled nanomaterials, has attracted significant attention due to their excellent physical and chemical properties. Self-assembled nanoplatforms can be designed to selectively deliver immunoadjuvants, therapeutic drugs, photosensitizers, and sonosensitizers, overcoming the limitations of traditional monotherapies. By utilizing these self-assembled nanoplatforms to synergistically combine cancer immunotherapy with photodynamic therapy (PDT), photothermal therapy (PTT), radiotherapy (RT), and sonodynamic therapy (SDT), it becomes possible to amplify and enhance the immune responses elicited by these localized treatments, thus offering new strategies for cancer therapy. In this review, we discussed various immunotherapy platforms based on the self-assembly of nucleic acids, peptides and proteins, metals, and supramolecules. We also highlight the significant research advancements over the past three years in the use of self-assembled nanomaterials for combination therapies centered on immunotherapy, aiming to provide valuable insights and references for ongoing tumor therapy research.
Advances of microneedle technology for the treatment of autoimmune diseases

Acta Pharmaceutica Sinica B. 2026, 16(4): 2232-2249.

Autoimmune diseases are characterized by an aberrant immune response directed against the body's own components, leading to immune dysfunction and loss of tolerance. This ultimately results in tissue damage and organ impairment. Despite the availability of a range of pharmacological agents for the treatment of autoimmune diseases, numerous challenges still remain. These include reduced bioavailability, first-pass metabolism, severe adverse effects, and low patient compliance associated with oral or injectable routes of administration. Microneedles (MNs) based delivery systems offer a promising alternative for transdermal drug administration, as they can circumvent the aforementioned limitations via the generation of microchannels in the skin in a minimally invasive manner with low pain. This review examines the applications and recent advances in MN systems for treating autoimmune diseases, focusing on six key areas: an overview of autoimmune diseases, current treatment modalities, an introduction to MNs, advantages of MNs for autoimmune disease treatment, advancements in MN-mediated therapies for diverse autoimmune diseases, and relevant MN technologies currently undergoing clinical trials. Additionally, it considers the prospective future advancements of MN systems in the management of autoimmune diseases.
Pathology-directed drug delivery strategies: How to overcome blood-brain barrier for the treatment of brain diseases

Acta Pharmaceutica Sinica B. 2026, 16(4): 2250-2281.

Despite the different degrees of blood-brain barrier (BBB) damage in diverse brain diseases, it remains a formidable barrier that restricts most drugs from penetrating the brain. A comprehensive understanding and elucidation of the disease-specific changes of BBB in various brain pathologies are essential for directing the customized brain-targeted drug delivery systems, potentially improving cerebral delivery efficiency and therapeutic efficacy. Hence, this review compared anatomical and physiological changes of BBB under healthy and pathological states and discussed the effects of these changes on cerebral delivery efficiency. Thereafter, a particular emphasis was placed on the pathology-directed drug delivery strategies tailored to different brain diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, stroke, and brain tumors. By combining insights from cutting-edge studies and emerging technologies, we proposed forward-looking suggestions on future directions to brain-targeted drug delivery, thereby improving the therapeutic efficacy and accelerating the translation from preclinical attempts into clinical practice.
SIM: Discovery of novel RNA-targeting argonautes by self-iterative learning from scarce data

Acta Pharmaceutica Sinica B. 2026, 16(4): 2282-2298.

The limited repertoire of experimentally validated RNA-targeting nucleases has constrained both mechanistic studies and the efficient discovery of novel enzymes for RNA biotechnology. This challenge is particularly pronounced for prokaryotic Argonaute (Ago) proteins, where the scarcity of confirmed RNA-targeting members and a lack of clarity regarding RNA specificity determinants hinder systematic exploration. Although machine learning offers a potential solution, its application is often impeded by the scarcity of labeled training data in this field. To address these limitations, we developed the self-iterative hierarchical ensemble model (SIM), which integrates hierarchical ensemble learning with a self-training strategy. This approach bypasses the dependency on large-scale experimental datasets, allowing SIM to iteratively expand its predictive capability from minimal initial labeled data. When applied to prokaryotic Agos, SIM identified six high-confidence RNA-targeting candidates, five of which were experimentally validated (83% success rate). Notably, SIM identified three uncharacterized Agos harboring a novel N-terminal domain, defining a previously unrecognized subclass. Biochemical and in vivo validations of Haloferax profundi Ago (HpAgo) confirmed its RNA cleavage activity and a distinctive RNA modification-sensing capability. We leveraged this latter finding to develop a rapid, cost-effective method for quantifying modified RNAs. Our study not only expands the repertoire of RNA-targeting tools but also establishes SIM as a generalizable framework for protein function prediction under data-scarce conditions. This work has broad implications for both RNA biotechnology and the application of machine learning in data-limited fields.
GEMap: A comprehensive gene essentiality map for drug discovery

Saisai Tian, Yixue Liang, Jinbo Zhang, Weishan Liang, Jinyuan Lu, Jiajia Ren, Bojian Lin, Ruijun Wu, Chengyang Guo, Weidong Zhang

Acta Pharmaceutica Sinica B. 2026, 16(4): 2299-2316.

Gene essentiality (synonymous with dependency) mapping reveals therapeutic vulnerabilities for intractable oncogenes, yet integrated platforms bridging CRISPR functional genomics with drug discovery remain limited. To address this gap, we developed GEMap, A Gene Essentiality-Guided Platform for Drug Discovery, by combining genome-wide CRISPR-Cas9 essentiality profiles (1912 screens across 1135 cancer cell lines) with multi-omics annotations, drug profiles and drug targets information (20,000+ compounds). GEMap can be used to (1) explore multimodal gene data (Dependency/Expression/CNV/Mutation) across cell lines and tissues; (2) prioritize context-specific therapeutic targets by quantifying differential genetic dependencies in molecularly stratified cancers, such as KRAS mutant-cancers; and (3) discover tailored treatments and drug candidates targeting particular gene using large-scale drug perturbation data and drug physical targets. To the best of our knowledge, GEMap represents the first platform bridging CRISPR-derived genetic dependencies with pharmacological responses and biological networks and establishes an open-access paradigm for accelerating precision oncology against undruggable targets. GEMap is available at https://web.biotcm.net/GEMap/.
Isoalantolactone induces AML pyroptosis and potentiates α-PD-1 efficacy by targeting selenoprotein TXNRD1

Acta Pharmaceutica Sinica B. 2026, 16(4): 2317-2331.

The suppressive microenvironment of AML limits anti-PD-1 efficacy, making pyroptosis induction a key strategy for its remodeling. Isoalantolactone (IAL), a naturally occurring small molecule, has been identified herein to inhibit cytosolic thioredoxin reductase1 (TXNRD1) and trigger pyroptosis in AML cells, thereby enhancing the efficacy of anti-PD-1 antibody therapy. Mechanistically, the α,β-unsaturated carbonyl group of IAL covalently bound to the selenocysteine residue at the position 498 (Sec⁴⁹⁸) of TXNRD1 through a Michael addition reaction. Clinical sample analysis revealed that TXNRD1 is overexpressed in AML, which correlates with poor prognosis. Additionally, we found that the TXNRD inhibitor auranofin has demonstrated good efficacy against AML. The inhibition of TXNRD1 activates the transcription factor peroxisome proliferator-activated receptor gamma (PPARγ), which, in turn, upregulates the transcription of caspase-3, subsequently increasing the cleavage of gasdermin E to induce pyroptosis via the non-classical pathway in AML cells. Additionally, enhanced caspase-3 activity promotes poly ADP-ribose polymerase 1 (PARP-1) cleavage and upregulates PD-L1 expression, thereby increasing sensitivity to anti-PD-1 monoclonal antibodies. Overall, the current study highlights a promising approach for augmenting therapy using anti-PD-1 monoclonal antibodies in AML by targeting TXNRD1 to induce pyroptosis and ameliorate the immunosuppressive microenvironment.
Engineered bacteria reprogram tumor microenvironment via cell senescence and neutrophil extracellular traps degradation

Acta Pharmaceutica Sinica B. 2026, 16(4): 2332-2356.

Attenuated Salmonella VNP20009 (VNP) shows promising anti-cancer therapeutic potential. Limited understanding of its anti-tumor mechanism has hindered broader clinical application. Recent studies have reported cellular senescence is involved in tumor progression; however, its critical role in VNP therapy remains elusive. Our study revealed that VNP exerts anti-tumor growth and anti-angiogenesis effects by inducing cellular senescence in tumor cells and vascular endothelial cells. While VNP-induced senescence inhibits tumor growth, it concurrently promotes neutrophil extracellular traps (NETs), which paradoxically enhance tumor progression. To address this challenge, we engineered VNP-SNase, a novel variant capable of releasing the DNA-degrading enzyme Staphylococcus aureus nuclease directly within tumors. VNP-SNase significantly inhibited NETs formation across multiple tumor types, effectively promoted anti-tumor immunity, and exhibited improved tumor suppression effects with enhanced biosafety. Our findings elucidate the critical role of cellular senescence in VNP therapy and propose targeting NETs as a strategic approach to enhance the efficacy of VNP-based cancer treatments.
Aberrant astroglial Kir4.1 activation in the anterior cingulate cortex disrupts neuronal excitability and social behavior

Zhengmao Li, Yixuan Zhang, Yan Chen, Ying Zhang, Yunlong Pan, Kerui Wang, Chen Li, Xiangyu Zhao, Weikang Hu, Yifan Luo, Jiawen Cheng, Hongzhen Zhang, Kohji Fukunaga, Yankai Xia, Jiandong Jiang, Xiuxiu Liu, Feng Han, Yingmei Lu

Acta Pharmaceutica Sinica B. 2026, 16(4): 2357-2374.

Prenatal herbicide exposure is increasingly linked to neurodevelopmental disorders, yet effective pharmacological interventions remain lacking due to unclear pathogenic mechanisms. Here, we demonstrate that prenatal exposure to glufosinate ammonium (GLA), a widely used herbicide, triggers autism-like behaviors, including social deficits and repetitive grooming, in offspring mice. Whole-brain c-Fos mapping, in vivo calcium imaging, and patch-clamp recordings identified hypoactive pyramidal neurons in the anterior cingulate cortex (ACC) as the neural substrate of these behavioral deficits in prenatally GLA-exposed offspring mice. Mechanistically, transcriptomic and multi-omics analyses revealed that astrocyte activation in the ACC drove Kir4.1 potassium channel upregulation, which suppressed CaMKIIα⁺ neuronal excitability via impaired astrocyte-neuron communication. Pharmacological inhibition of astroglial Kir4.1 not only restored neuronal activity but also rescued social deficits in GLA-exposed offspring, underscoring Kir4.1’s pivotal role in ACC dysfunction. Our study uncovers a novel astrocyte-neuron axis underlying herbicide-induced neurodevelopmental impairments and identifies Kir4.1 as a therapeutic target for environmental factor-associated autism.
FTO-mediated m⁶A depletion drives prenatal prednisone exposure-induced cortical neurogenesis deficits and long-term anxiety-depression-like behaviors in offspring

Acta Pharmaceutica Sinica B. 2026, 16(4): 2375-2395.

Prednisone is widely used to treat pregnancy-complicated autoimmune diseases, but the impact of prenatal prednisone exposure (PPE) on offspring neurodevelopment is unclear. Clinical follow-up using the Ages and Stages Questionnaires (ASQ:SE-2 and ASQ-3) revealed a strong association between PPE and neurodevelopmental abnormalities. In a rat model, PPE significantly inhibited the proliferation and differentiation of cortical radial glial cells (RGCs), impairing cortical neurogenesis and leading to anxiety- and depression-like behaviors. Mechanistically, PPE upregulated fat mass and obesity-associated protein (FTO) nuclear recruitment in RGCs, depleting N⁶-methyladenosine (m⁶A) modifications and stabilizing Crebbp/Ep300 mRNA, which activated genes related to cell cycle arrest and neuronal differentiation via histone 3 at lysine 27 acetylation (H3K27ac) modifications. The key role of FTO in PPE-induced neurodevelopmental impairments was confirmed using Ep300 shRNA, Fto overexpression lentivirus, and a conditional Fto knockout mouse model (Ftofl/fl; Nestin-Cre). Notably, early postnatal neuregulin-1 supplementation promoted RGCs proliferation and alleviated behavioral abnormalities.

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