Acta Pharmaceutica Sinica B

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Anacyphrethines A and B as potent analgesics: Multiple ion channel inhibitors with an unprecedented chemical architecture

Acta Pharmaceutica Sinica B. , (): 3725-3737.

Multi-target analgesics with minimal side effects and high efficacy are a key research focus in addressing the global pain crisis. Using a molecular networking approach, five pairs of potent analgesic alkaloid enantiomers were isolated from the roots of Anacyclus pyrethrum (A. pyrethrum). Their structures were elucidated by comprehensive spectroscopic data analysis, including LR-HSQMBC and ¹H–¹⁵N HMBC, quantum ¹³C NMR DP4+ and ECD calculations, and single-crystal X-ray diffraction analysis. Anacyphrethines A (1) and B (2) are highly conjugated and polymethylated 6/6/6/6/5/7/5/5-fused octacyclic tetraazabic alkaloids possessing an unprecedented 8,14,18,24-tetraaza-octacyclo[16.8.2.1¹,²³.0⁴,²⁸.0⁵,¹⁷.0⁹,¹⁶.0¹¹,¹⁵.0²¹,²⁷] nonacosane motif. Their biosynthetic pathways are proposed involving key aldol, hydroamination, and Schiff base reactions. All isolates showed potent analgesic effects in vivo. Even at a lower dose of 0.2 mg/kg, (±)-1 and (+)-1 still exhibited more potent analgesic activities than morphine. Interestingly, the racemic mixture (±)-1 showed stronger analgesic effect than either pure enantiomer alone at higher doses of 5 and 1 mg/kg; while, (±)-1 showed significant analgesic activities comparable to (+)-1 at lower doses of 0.2 and 0.04 mg/kg. (+)-1 had stronger analgesic effect than (-)-1 at five tested does. Further tests on 44 analgesic-related targets demonstrated that (+)-1 showed significant inhibitory effects against many ion channels such as TRPM8, Kv1.2, Kv1.3, and Cav2.1 with IC₅₀ values of 1.10 ± 0.26, 4.20 ± 0.07, 2.20 ± 0.24, and 10.40 ± 0.69 μmol/L, respectively, while (-)-1 primarily inhibited TRPC6, Kv1.2, and Kv1.3 ion channels with IC₅₀ values of 0.81 ± 0.05, 0.91 ± 0.04, and 1.50 ± 0.13 μmol/L, respectively, without affecting the opioid receptors, suggesting their non-opioid analgesic potentials. The molecular dockings provided structural guidance to develop potent non-opioid analgesics.
The role of non-coding RNAs in regulating R-loop dynamics in cancer: Mechanisms and therapeutic implications

Acta Pharmaceutica Sinica B. 2026, 16(8): 4749-4769.

R-loops, RNA:DNA hybrids formed during transcription, play critical roles in regulating gene expression and maintaining genome stability. Dysregulation of R-loop formation and resolution has been linked to genomic instability, a hallmark of cancer. Recent advances have highlighted the pivotal role of non-coding RNAs (ncRNAs), particularly long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), in modulating R-loop dynamics, influencing tumorigenesis, and contributing to therapeutic resistance. These ncRNAs participate in the formation, stabilization, and resolution of R-loops, which in turn regulate critical processes such as transcriptional regulation, DNA repair, and chromatin architecture. For example, circRNAs such as circSMARCA5 and circDMD have been shown to induce R-loop formation, influencing gene expression and sensitizing cancer cells to chemotherapy. Conversely, lncRNAs such as TUG1 and NEAT1 regulate R-loop resolution, maintaining genome stability and enhancing tumor cell survival. The interaction between ncRNAs and R-loops offers promising avenues for targeted therapeutic strategies aimed at restoring R-loop balance to improve cancer treatment outcomes. This review provides an in-depth exploration of the molecular mechanisms by which ncRNAs modulate R-loop dynamics and discusses their potential as biomarkers and therapeutic targets in oncology. Furthermore, we highlight the challenges and future directions in translating these findings into clinical applications.
Inflammation in atherosclerosis: Drivers, mechanisms and therapies

Acta Pharmaceutica Sinica B. 2026, 16(8): 4770-4807.

Atherosclerosis has traditionally been considered a lipid-driven disease. However, emerging evidence highlights the central role of inflammation in the development of atherosclerosis. Multiple cell types, including endothelial cells, macrophages, and other immune cells, interact within lesions to form a chronic inflammatory microenvironment. Unhealthy lifestyle, smoking and metabolic disorders like hyperlipidemia, hyperglycemia, and their derived pro-atherogenic products drive vascular inflammation. Recent evidence reveals that high-sensitivity C-reactive protein surpasses LDL-cholesterol in predicting future cardiovascular risk. Combining lipid-lowering with anti-inflammatory therapies significantly reduces event recurrence, underscoring the need for targeted drugs. Promising results have emerged from trials of anti-inflammatory agents. Statins and other lipid-lowering drugs also exhibit anti-inflammatory properties. However, cholesterol-independent strategies face challenges like infection risk from immunosuppression, requiring extensive safety evaluation. Enhancing intrinsic resilience mechanisms is a promising alternative in combating vascular inflammation and atherosclerosis. High-throughput screening accelerates drug development, while induced pluripotent stem cell-derived vascular organoids better simulate human atherosclerosis pathobiology, improving preclinical predictions. Research on organ interaction networks and trained immunity offers novel therapeutic targets. In this comprehensive review, we provide a state-of-the-art synthesis of the drivers, mechanisms, and potential therapies of atherosclerosis by targeting inflammation, with an aim to reducing residual cardiovascular risk in the post-statin era.
HIFs: The central drivers of tumors and their role as molecular switches in targeted therapy?

Acta Pharmaceutica Sinica B. 2026, 16(8): 4808-4828.

Hypoxia-inducible factors (HIFs) serve as the central signaling hub within the hypoxic tumor microenvironment, coordinating tumor proliferation, metastasis, and therapy resistance. This protein family comprises HIF-1α, HIF-2α, HIF-3α, and HIF-1β, with distinct subcellular localization patterns reflecting their isoform-specific oxygen-sensing mechanisms. Tumor-associated HIF expression is regulated through a multifaceted network involving non-coding RNAs (ncRNAs), mitochondrial metabolites, and post-translational modifications (PTMs). These aberrantly expressed HIFs then orchestrate biologically important processes including metabolic reprogramming, angiogenesis, and pro-tumorigenic inflammation. It is important to note that current evidence regarding HIF-3α function remains limited and requires further validation in vivo. This review first systematically deciphers the mechanisms governing HIF dysregulation in tumors, before elucidating the key biological processes involved. We then synthesize advances in HIF-targeting inhibitors. These pivotal findings provide a solid theoretical foundation and novel insights for both anticancer therapies targeting this critical “molecular switch” and translational research focusing on HIFs as promising therapeutic targets.
Telomere-associated non-malignant pulmonary diseases: Pathogenic mechanisms and therapeutic strategies

Acta Pharmaceutica Sinica B. 2026, 16(8): 4829-4853.

Telomeres and telomerase have been extensively implicated in the cellular processes of aging and inflammation. Recent studies have shown that telomere length (TL), the shelterin complex, and telomerase dysfunction are closely related to non-malignant pulmonary diseases, including interstitial lung diseases (ILD), chronic obstructive pulmonary disease (COPD), and asthma. Short telomere defects with or without mutations in telomere maintenance genes and telomerase are relatively common, affecting the progression of non-malignant pulmonary diseases, explaining disease susceptibility, and revealing clinically relevant manifestations. In this review, we examine the biological characteristics and functions of telomeres and telomerase, and investigate the intricate relationship between changes in TL and mutations in telomerase genes in non-malignant pulmonary diseases after a detailed associated literature review. Subsequently, we focus on the clinical features of non-malignant pulmonary diseases related to dysfunctional telomeres/telomerase, as well as the potential molecular mechanisms underlying these associations, along with the current status of therapeutic interventions. Finally, we delineate current knowledge gaps and transformative opportunities in telomere biology research, with a focus on bridging molecular discoveries to clinical innovations for telomere-associated non-malignant pulmonary diseases, aiming to accelerate the development of precision diagnostic tools and mechanism-based therapeutics.
A destination-driven framework for nanoparticle-enabled targeted protein degradation

Yazhen Wang, Xue Xia, Shengwei Xie, Fan Tong, Wen Liu, Huile Gao

Acta Pharmaceutica Sinica B. 2026, 16(8): 4854-4875.

Targeted protein degradation (TPD) offers a revolutionary paradigm to eliminate disease-driving proteins. Given the distinct technical requirements and challenges associated with degrading intracellular versus extracellular proteins, we classify existing TPD strategies based on subcellular localization into two categories: intracellular TPD (iTPD), which targets proteins within the cytoplasm and nucleus, and extracellular TPD (eTPD), which focuses on membrane-bound and secreted proteins. This destination-based framework facilitates precise technology selection and rational design by aligning methods with the biological context of their targets. However, the clinical translation of TPD remains constrained by a significant “delivery gap”. Current nanotechnological approaches are often discussed monolithically, despite the fundamentally distinct delivery requirements between iTPD and eTPD. For iTPD, the primary nanocarrier role is to confer fundamental drug-like properties to overcome systemic pharmacokinetic hurdles. Conversely, for eTPD, the nanoplatform's chief function is to engineer cellular engagement, enhance internalization, and orchestrate correct intracellular trafficking to the lysosome. This review will dissect the distinct challenges inherent to each “geographic” space and detail the tailored nano-playbooks being developed to address them. We will further explore the convergence of these two worlds and the emergence of nanoparticles as intrinsic degraders. Ultimately, we argue that a location-aware design philosophy is essential for unlocking the full therapeutic potential of TPD.
Tuning protein corona on nucleic acid nanodrugs for targeted delivery

Acta Pharmaceutica Sinica B. 2026, 16(8): 4876-4897.

Nanoparticle-based delivery systems hold transformative potential for nucleic acid therapeutics. However, the fate of nucleic acid nanodrugs (NANDs) in vivo differs significantly from that observed in vitro, directly impacting their therapeutic efficacy. Upon introduction into biological fluids, NANDs rapidly adsorb proteins onto their surfaces, forming an assembled adsorption layer known as the protein corona (PC). This PC critically influences the physicochemical properties of NANDs and consequently governs their subsequent biological interactions. This review comprehensively introduces the mechanisms underlying PC formation, including dynamic adsorption kinetics and influential physicochemical and environmental factors. We further discuss how the PC modulates key in vivo processes, including penetration of gastrointestinal mucus and epithelial barriers, stability during systemic circulation, biodistribution and cellular tropism, as well as cellular uptake and endolysosome escape of nucleic acid therapeutics. While the PC may obscure engineered ligands and accelerate off-target clearance, it also offers opportunities to harness endogenous proteins for targeting. We therefore highlight emerging design strategies aimed at actively steering PC composition to achieve targeted nucleic acid delivery and enhanced therapeutic outcomes. Finally, we present prospects for translating fundamental knowledge of PC formation and function into the rational design of next-generation engineered nanocarriers for targeted NANDs applications.
Nanocarrier-based delivery of Pt(IV) compounds for chemoimmunotherapy and theranostics: Advances, challenges, and prospects

Daniil Spector, Roman Akasov, Vladislav Bykusov, Georgy Karetnikov, Anastasia Zharova, Elena Beloglazkina, Olga Krasnovskaya

Acta Pharmaceutica Sinica B. 2026, 16(8): 4898-4977.

Nanocarrier-based delivery of platinum compounds represents the next generation of platinum-based chemotherapy, which is a first-line treatment for many types of tumors. Despite the significant success of Pt(IV) prodrugs as effective antitumor agents, the therapeutic efficacy of most of the reported prodrugs is limited due to rapid biodegradation in the bloodstream and limited accumulation in the tumor. To overcome these limitations, various types of nanomedicines have been developed as drug delivery systems for Pt(IV) prodrugs, with those demonstrating significantly enhanced antitumor effects due to passive and active tumor targeting, stimulus-responsive drug release, effective synergistic therapy, the ability to induce immunogenic cell death, stimulate native and adaptive immunity, and preventing tumor recurrence. Also, the design of Pt(IV)-based theranostic nanoagents opens up photothermal, fluorescent, and photoacoustic imaging modalities for real-time monitoring of drug delivery and therapeutic response. The ability to harness photocontrolled chemotherapy along with immunotherapy, PDT, and PTT holds immense promise for synergistic anticancer effects. In the present review, we highlighted recent advances in the design of Pt(IV)-based NPs reported in 2022-2025 with the focus on the further development of this fast-growing research area.
Nanobodies targeting SARS-CoV-2 variants

Acta Pharmaceutica Sinica B. 2026, 16(8): 4978-4997.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a beta-coronavirus, caused the recent global Coronavirus Disease 2019 (COVID-19) pandemic. Among the virus-encoded proteins, the surface spike (S) protein is critical for viral entry, membrane fusion, and pathogenesis, and its receptor-binding domain (RBD) initiates viral entry by binding to a cellular receptor. This makes the S an important therapeutic target for COVID-19. SARS-CoV-2 mutates frequently, giving rise to five major variants of concern, among which the Omicron variant and its subvariants are less sensitive to current therapeutic antibodies. The first part of this review describes the main protein constituents of SARS-CoV-2 and their functions, the S protein-mediated viral entry and fusion processes, and the main SARS-CoV-2 variants. Nanobodies are single-domain antibodies with high target-binding affinity, strong stability, and low production costs, whose small size facilitates their access to protein regions that are inaccessible to conventional antibodies. Thus, in the second part, we comprehensively review SARS-CoV-2-targeting nanobodies, including those that bind specifically to the RBDs of the S proteins, non-RBD S proteins, and non-S proteins of variants and subvariants of SARS-CoV-2, with the hope that this information will be valuable for the generation of novel SARS-CoV-2-targeting nanobodies with improved potency against COVID-19.
Phase change nanodroplets: Challenges and clinical potential

Xiaoyu Wang, Roman Barmin, Roger Molto Pallares, Anne Rix, Fabian Kiessling

Acta Pharmaceutica Sinica B. 2026, 16(8): 4998-5015.

Phase change nanodroplets (PCND) consist of a liquid fluorocarbon core, which vaporizes into gas upon energy excitation, and a stabilizing shell. Through this phase-change property, PCND combine nanoparticle-like stability and pharmacokinetics, such as tissue extravasation and uptake by the mononuclear phagocyte system, with distinctive microbubble-like capabilities, namely ultrasound contrast enhancement and energy-triggered therapeutic action. PCND serve both as highly sensitive imaging agents, from molecular imaging to high-resolution vascular mapping, and as versatile therapeutics, used for example for thrombolysis, tissue ablation, biofilm removal, immunomodulation, and drug delivery. This review article provides a focused review of the biological behavior of PCND, including blood half-life, biodistribution, clearance pathways, and tumor accumulation, following a brief overview of the key physicochemical features that shape their in vivo fate. By comparing data across studies, we identify major inconsistencies in reported pharmacokinetics and highlight critical knowledge gaps, particularly regarding safety data. We further summarize advances in PCND-enabled imaging and therapy, and propose strategies to strengthen formulation design, biological evaluation, and stimulation protocols to support future clinical translation. Overall, PCND hold strong potential as a versatile theranostic platform. Continued systematic and clinically focused research is expected to accelerate their path toward clinical translation.

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