Acta Pharmaceutica Sinica B

Sonic priming and biomimetic synergy: A paradigm shift in solid tumor therapy

Acta Pharmaceutica Sinica B. 2026, 16(5): 3251-3253.

Small molecules modulate the biomolecular condensates and liquid-liquid phase separation

Acta Pharmaceutica Sinica B. 2026, 16(5): 2756-2772.

Phase separation of biological macromolecules is a ubiquitous cellular mechanism for concentrating and compartmentalizing biochemical reactions. Emerging evidence reveals that biomolecular condensates formed via liquid-liquid phase separation (LLPS) play integral roles in diverse physiological processes, including gene expression and intracellular signaling, enabling rapid and delicate cellular responses. Dysregulation of phase separation is increasingly implicated in the pathogenesis of major diseases, ranging from neurodegenerative disorders and cancers to viral infections and aging. Consequently, deciphering the molecular mechanisms governing LLPS and developing strategies for its pharmacological modulation, particularly via small molecules, represent promising therapeutic targets offering novel approaches for disease intervention. In this review, we provide a concise overview of biomolecular condensates formation and their functions in diseases regulation. Mainly, we catalog commonly employed tool compounds, reported small-molecule modulators of LLPS, and related clinical progress within this rapidly evolving research area. Furthermore, we integrate recent technological breakthroughs in LLPS to envision the future trajectory and therapeutic potential of this field.

Urate transporters: Structural mechanisms and therapeutic opportunities in drug development

Acta Pharmaceutica Sinica B. 2026, 16(5): 3243-3248.

Agonist-specific FPR1 conformational change prevents receptor recycling and promotes targeted protein degradation

Acta Pharmaceutica Sinica B. 2026, 16(5): 3043-3058.

Recycling of internalized cell surface receptors is critical for membrane transport and receptor-mediated signaling. Formyl peptide receptor 1 (FPR1) plays important roles in host defense and inflammatory tissue injury. Here we report that fMet-Leu-Phe-Cys (fMLFC), a peptide agonist of FPR1, prevents recycling of internalized FPR1 and diverts it to the late endosome and lysosome for degradation. In contrast, FPR1 bound to the classic ligand fMLF interacts with RAB11 and SNX17, facilitating its recycling back to the cell surface. We determined a cryo-EM structure of fMLFC-bound FPR1-Gi complex. Alanine substitutions of key residues that interact with fMLFC (F102A, T177A, F178A) improved FPR1 recycling. Using a FlAsH-NanoBRET-based FPR1 biosensor, the fMLFC-induced receptor conformational change was found to be different from the fMLF-induced conformational change. fMLFC stimulation reduced FPR1 cell surface expression, along with reduced acute lung injury in LPS-treated mice. Our findings suggest that fMLFC is a chemical knockdown agent that promotes targeted protein degradation and reduces FPR1-mediated inflammation.

Biomimetic liposomes synergize with high-intensity focused ultrasound to induce ferroptosis in tumors

Ruizhe Xu, Xuejing Li, Xiaomin Su, Xifeng Qin, Ying He, Siyu Wang, Yue Liu, Jiayi Wu, Ting Wang, Mingyang Liu, Boshu Ouyang, Jia Li, Wuli Yang, Bo Zhang, Zhiqing Pang

Acta Pharmaceutica Sinica B. 2026, 16(5): 3224-3242.

The efficient targeted delivery and on-demand release of nanomedicines still present significant challenges in tumor therapy. In the present study, we developed a novel strategy of tumor ferroptosis therapy through the synergistic effect of nanomedicines (biomimetic liposomes) and a medical device (high-intensity focused ultrasound, HIFU). It was found that HIFU irradiation induced heightened expressions of CD44 and reactive oxygen species (ROS) in tumor cells by 1.43-fold and 2.64-fold, respectively. This allowed the gambogic acid-loaded, platelet-mimicking liposomes (PLip) to more precisely target the tumor cells through the interaction of CD44 and P-selectin on the PLip and subsequently ROS-responsively release the drug from PLip, thus effectively killing tumor cells. Crucially, gambogic acid also significantly enhanced ROS production, leading to lipid peroxidation and augmented ferroptosis induced by HIFU. In summary, HIFU demonstrates immense potential in synergizing with nanomedicines to combat tumors.

Oridonin as a novel KDM5C inhibitor alleviates clonal hematopoiesis-induced cardiac aging via H3K4me3-dependent SASP suppression

Acta Pharmaceutica Sinica B. 2026, 16(5): 3001-3025.

TET2-mediated clonal hematopoiesis of indeterminate potential (CHIP) is a known cardiovascular risk factor, but its role in cardiac aging and potential for pharmacological intervention remain unclear. Herein, Mendelian randomization using large-scale genome-wide association studies (GWAS) data assessed CHIP's causal impact on aging and cardiovascular disease that revealed significant causal associations between TET2-CHIP, CVD, and aging biomarkers. Transcriptome-guided screening identified oridonin as a candidate compound reversing CHIP- and aging-associated gene signatures. Multi-tiered target prediction combining chemical structure-based algorithms and transcriptomic correlation identified KDM5C as a key target, validated by enzymatic inhibition and surface plasmon resonance assays. In vivo and in vitro administration of oridonin significantly ameliorated cardiac dysfunction and pathological remodeling in the CHIP model. Epigenetic regulation was profiled via ChIP-seq and RNA-seq, focusing on H3K4me3-mediated transcription. Tet2⁺/⁻BMT mice exhibited age-progressive myocardial fibrosis, inflammation, senescence, and functional decline. Mechanistically, oridonin inhibited KDM5C histone demethylase, restored H3K4me3 levels, and activated the SIRT2 anti-aging pathway. Rescue experiments using gene overexpression and recombinant protein supplementation confirmed the functional role of the KDM5C-H3K4me3-SIRT2-S100A8 axis in mediating oridonin's effects. Overall, TET2-driven CHIP promotes cardiac aging, as evidenced by human genetic analyses and long-term BMT models. Oridonin, by inhibiting KDM5C and restoring H3K4me3-dependent SIRT2 signaling, mitigates CHIP-induced myocardial aging.

Analysis of intratumoural bacteria: Opportunities and challenges for cancer therapy

Acta Pharmaceutica Sinica B. 2026, 16(5): 2877-2902.

Intratumoural bacteria have been shown to play conflicting roles within tumours, especially in the modulation of immune responses. Moreover, bacteria have been linked to a variety of cancer types and have different prognostic values depending on the cancer. This heterogeneity is not only shaped by tumour molecular subtypes, spatial location, cancer progression stage, genetic alterations, and the presence of multiple subclones, but is also influenced by variations in angiogenesis, oxygen levels, microbial sources, endocytosis and micropinocytosis. In this review, we describe the diversity of intratumoural bacteria across 25 cancer types covering an extensive spectrum of analyzed intratumoural bacteria. Furthermore, the dual roles and mechanisms of their involvement in tumour progression and anticancer activity are summarized. Additionally, interventions and applications of engineered bacteria in cancer therapy, especially strategies used in clinical trials, are illustrated. This work describes the roles of intratumoural bacteria and their metabolic byproducts as regulators within the tumour microenvironment and highlights the potential translation of bacteria for cancer therapy.

Hypoxia-selective targeting of eEF1A1: A promising therapeutic strategy for triple-negative breast cancer

Acta Pharmaceutica Sinica B. 2026, 16(5): 3249-3250.

Extracellular vesicles: Revolutionizing targeted therapy for ischemic stroke

Ju Bai, Jingshu Yang, Wei Liu, Bin Han, Shaoyan Jiang, Jinping Sun, Hongzhao Qi

Acta Pharmaceutica Sinica B. 2026, 16(5): 2838-2876.

Ischemic stroke (IS) remains a leading cause of global death and disability, with treatment effectiveness limited by its complex mechanisms, which include blood-brain barrier (BBB) disruption, neuroinflammation, excitotoxicity, oxidative stress, and cell death. This review summarizes emerging research on extracellular vesicle (EV)-based therapies for IS. EVs, sourced from animals, plants, and microbes, have unique benefits as natural nanocarriers, such as inherent BBB permeability, biocompatibility, and the ability to deliver multiple therapeutic cargos (like miRNAs, proteins, and drugs). We evaluate how EVs target key IS issues: (1) restoring BBB integrity by stabilizing tight junctions (TJs) and reducing matrix metalloproteinases (MMPs), (2) modulating microglia to reduce neuroinflammation, (3) decreasing excitotoxicity, (4) scavenging reactive oxygen species (ROS) to lessen oxidative stress, and (5) inhibiting apoptosis, ferroptosis, and other cell death pathways. Additionally, engineered EVs, such as antibody-conjugated or magnetically guided types, exhibit improved targeting and treatment accuracy, yielding promising results. Despite significant preclinical promise, clinical application faces challenges in standardization, scalable production, and delivery improvement. EVs offer a transformative, multi-targeted approach with the potential to overcome current limitations in IS treatment.

Multistage responsive microneedle delivery system loaded oncolytic virus for topical therapy of melanoma

Acta Pharmaceutica Sinica B. 2026, 16(5): 3211-3223.

Melanoma, the most aggressive form of skin cancer, remains a formidable therapeutic challenge. While oncolytic viruses (OVs) exhibit promising antitumor potential, their efficacy is often limited by insufficient intratumoral viral replication, poor tissue penetration, and the immunosuppressive tumor microenvironment (TME). Herein, a multistage microneedle (MN-OJ) system designed to amplify both local oncolysis and systemic antitumor immunity mediated by oncolytic adenovirus (OA) in melanoma. The dissolvable MN base facilitates rapid OA delivery, inducing tumor cell lysis and subsequent release of tumor-associated antigens to prime T-cell responses. Concurrently, the degradable MN tip enables sustained release of JQ1, which enhances OA replication, modulates lactic acid levels and PD-L1 expression, thereby reprogramming the immunosuppressive TME to promote T-cell infiltration and cytotoxicity. In murine models, MN-OJ demonstrated potent inhibition of both primary and distal tumors, without systemic toxicity. This innovative platform combines immediate tumor destruction with sustained immune modulation, offering a promising clinical approach for melanoma therapy.