Acta Pharmaceutica Sinica B

SIM: Discovery of novel RNA-targeting argonautes by self-iterative learning from scarce data

Shuze Peng, Feiming Huang, Nuolan Li, Karl Luigi Loza Vidaurre, Luer Chen, Yu Yang, Jiaying Hu, Yanyu Kou, Wei He, Shiwei Wang, Lei Shi, Kehao Tao, Bo Sun, Xiaoxuan Song, Hao Yang, Hainan Zhang, Lin Yang, Zixin Deng, Yanqiang Han, Yan Feng, Qian Liu, Jinjin Li

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.

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.

GEMap: A comprehensive gene essentiality map for drug discovery

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/.

Self-assembled nanoplatforms for cancer immunotherapy: Principles, progress and perspectives

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.

Lipid-based nanosystems for atherosclerosis treatment: Evolving approaches and novel therapeutic strategies

Acta Pharmaceutica Sinica B. 2026, 16(4): 2153-2173.

Atherosclerosis, the leading cause of cardiovascular diseases, has become increasingly prevalent worldwide, driving the need for innovative therapeutic strategies to improve clinical outcomes. Lipid-based nanosystems have emerged as promising drug delivery platforms due to their biocompatibility, versatility, and proven clinical track records. Among them, traditional systems such as liposomes have been extensively applied in atherosclerosis therapy, primarily for their well-established safety profile and their capacity to deliver both hydrophilic and hydrophobic agents. However, emerging research has expanded the scope of lipid-based nanosystems to include lipid nanoparticles, lipoprotein-based nanosystems, cell membrane-coated nanosystems, and so on. These systems have demonstrated great promise in addressing the complex and heterogeneous nature of the disease. This review aims to provide a comprehensive overview of lipid-based nanosystems, from traditional formulations to cutting-edge innovations, and their evolving applications in the treatment of atherosclerosis. We also discuss the challenges associated with the clinical translation of these systems, as well as future prospects for developing more effective and personalized therapeutic strategies. In conclusion, lipid-based nanosystems provide a promising option for atherosclerosis treatment, potentially driving the progress of novel therapeutic strategies.

Editorial of special column of hot topic reviews in drug delivery (II)

Wei Wu, Wei He, Zongming Zhao

Acta Pharmaceutica Sinica B. 2026, 16(4): 1802-1803.

Deep eutectic solvents@enteric technology for orally delivering anticoagulant macromolecule drug

Acta Pharmaceutica Sinica B. 2026, 16(4): 2553-2569.

Low-molecular-weight heparin (LMWH) is one of the most clinically used anticoagulants to improve venous circulation. However, LMWH requires repeated injections, leading to poor medication compliance. Herein, we developed a deep eutectic solvents (DESs)@enteric technology, an intestinal absorption promotion platform, for the oral administration of LMWH. DESs with geranic acid (Ge) and choline (Ch) were first synthesized and characterized. Then, the DES-LMWH complex was prepared with a DES₂:₁ (Ge and Ch in a 2:1 molar ratio), demonstrating superior intestinal absorption and high biocompatibility. Finally, DES-LMWH was granulated and loaded into an enteric capsule. In vitro, DESs reversibly opened the tight junctions between intestinal epithelial cells, facilitating the paracellular transport of LMWH. In vivo, the DES-LMWH oral enteric capsule demonstrated an absolute bioavailability of 19.93%, reaching the venous thromboembolism (VTE) prophylaxis threshold and reducing the embolization area by 52.01% in a FeCl₃-induced rat femoral venous thrombosis model. In conclusion, DES@enteric technology effectively enhances the oral absorption of LMWH and holds promising translational potential.

Advances of microneedle technology for the treatment of autoimmune diseases

Ying Chen, Yanping Fu, Xinyu Wen, Minglong Chen, Linghui Dian, Tingting Peng, Chuanbin Wu, Chao Lu, Guilan Quan

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.

An oral immune enhancer with excellent biocompatibility for effectively strengthening body’s immunity and treating cancer

Acta Pharmaceutica Sinica B. 2026, 16(4): 2474-2497.

Enhancing immunity offers a versatile yet effective strategy for treating or preventing diseases. Here, we obtained a new polysaccharide (AFP-80) from Anoectochilus formosanus that unexpectedly stimulated immune systems without causing any detectable adverse effects. AFP-80 was applied to encapsulate Lactobacillus plantarum (LP), a probiotic with immunoregulatory properties, through bridging by Fe³⁺-tannic acid network (Fe-TA) to establish an oral immune enhancer (LP@Fe-TA@AFP-80). Upon oral administration, LP@Fe-TA@AFP-80 colonized intestines with high survival rates, aided by gastrointestinal stress-shielding and adhesive properties of AFP-80 and Fe-TA, respectively, leading to synergistic immuno-enhancing effects through combining AFP-80 and live LP. As a result, in immunocompromised mice, LP@Fe-TA@AFP-80 significantly renovated immune functions, which was deciphered to be closely associated with the rebalance of gut microbiota toward a profile with positively-immunoregulatory bacteria enriched as well as the involvement of peroxisome proliferators-activated receptor signaling pathway activation. Additionally, LP@Fe-TA@AFP-80 effectively treated cancer, e.g., 4T1 breast and MC38 colon tumors, either alone or in combination with immune checkpoint blockade therapy, by remodeling tumor immune microenvironment and gut microbiota. Moreover, LP@Fe-TA@AFP-80 demonstrated excellent biocompatibility, as directly revealed by negligible biotoxicity even after 6 months of consecutive ingestion, highlighting its great potential to be implemented into people’s daily life for disease prevention.

Aberrant astroglial Kir4.1 activation in the anterior cingulate cortex disrupts neuronal excitability and social behavior

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.