Acta Pharmaceutica Sinica B

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Tuning mechanical softness as a design principle in drug delivery: A biomechanical perspective

Acta Pharmaceutica Sinica B. 2026, 16(3): 1336-1367.

The in vivo performance of drug delivery systems (DDS) is profoundly dictated by their interactions with the biomechanical environment. Consequently, actively tuning the mechanical properties of DDS, such as softness and deformability, has emerged as an important design principle for enhancing their therapeutic efficacy. By intelligently adapting to the body's complex biomechanical system, these engineered DDS can orchestrate specific biological responses, such as enhanced tissue penetration, prolonged systemic circulation, and even regulated cellular signaling pathways through mechanotransduction. This review systematically explores, from a biomechanical perspective, how to optimize the behavior of DDS in the complex biological environments by actively designing their mechanical properties. We discuss how this principle was applied across diverse platforms, including coacervates, hydrogels, Pickering emulsions, extracellular vesicles, and liposomes, to achieve enhanced therapeutic behavior for treating challenging diseases like cancer, chronic wounds, and neurological disorders. By focusing on these tunable mechanical properties, this review aims to provide a theoretical framework and insights for the future development of DDS with improved adaptability and therapeutic efficacy in clinical settings.
Membrane-derived biomimetic nanovesicles in anti-tumor immunotherapy: Advances and outlook

Acta Pharmaceutica Sinica B. 2026, 16(3): 1388-1420.

Membrane-derived biomimetic nanovesicles have emerged as a promising platform in cancer immunotherapy due to their intrinsic biocompatibility, functional plasticity, and capability to modulate immune responses. By integrating various immunotherapeutic agents, including immune checkpoint inhibitors, tumor antigens, and immunostimulatory adjuvants, these vesicles can be engineered to mimic natural immune communication and overcome key barriers in the tumor immune microenvironment. This review summarizes recent advances in the design, functionalization, and application of biomimetic nanovesicles for anti-tumor immunity. We particularly highlight strategies that harness these vesicles to enhance innate and adaptive immune responses, reverse immune suppression, and synergize with existing immunotherapy modalities. Furthermore, we discuss the challenges associated with biosafety, large-scale manufacturing, and clinical translation. Continued innovation in vesicle engineering and immunological modulation will be crucial for transforming biomimetic nanovesicles into viable next-generation cancer immunotherapeutics.
Metal-polyphenol network-based multifunctional materials for tumor therapy: Intrinsic properties, advances, and applications

Acta Pharmaceutica Sinica B. 2026, 16(3): 1421-1448.

Metal-polyphenol networks (MPNs), a novel class of nano-biomaterials, have recently emerged as promising candidates for tumor diagnosis and therapy due to their unique chemical tunability, excellent biocompatibility, and synergistic multifunctionality. Notably, MPNs can be synthesized via one-step or multi-step approaches, allowing precise control over their morphology, size, and drug-loading capacity. The versatility of MPNs is further demonstrated by their ability to integrate multiple therapeutic modalities, including chemotherapy, photothermal therapy, photodynamic therapy, and chemical dynamic therapy. Furthermore, through surface modification with targeted molecules, MPNs enable tumor-specific targeting while facilitating real-time therapeutic monitoring via multimodal imaging. Additionally, MPNs exhibit excellent biocompatibility and superior biodegradability, making them highly suitable for biomedical applications. This review systematically explores MPN synthesis strategies and physicochemical properties. It then comprehensively analyzes MPN-based biomaterials and their tumor therapeutic mechanisms. Furthermore, we evaluate the challenges in MPN clinical translation and propose future perspectives for precise tumor treatment using MPN-based platforms. Ultimately, this review highlights the transformative potential of MPNs in advancing tumor theranostics and lays the foundation for their future clinical applications.
Inhibition of PGK1 enhances sensitivity to tyrosine kinase inhibitor in T315I-mutant leukemia

Acta Pharmaceutica Sinica B. 2026, 16(3): 1449-1465.

Phosphoglycerate kinase 1 (PGK1) is traditionally recognized for its pivotal role in glycolysis. Our findings reveal that PGK1 also functions as a protein kinase phosphorylating valosin-containing protein (VCP) at S746, which subsequently reduces Beclin 1 deubiquitination and impairs autophagy. Inhibition of PGK1 initiates autophagy in T315I-mutant chronic myeloid leukemia (CML) cells, thereby enhancing their sensitivity to first-generation Tyrosine Kinase Inhibitor (TKI) imatinib and third-generation TKI ponatinib. Despite the significant clinical implications, few PGK1-targeting inhibitors have been approved for clinical use to date. Through a comprehensive high-throughput screening of ∼20,000 natural compounds, we identified flavonoid as potent inhibitors of the enzymatic activity of PGK1. Subsequent structural optimization of these flavonoid derivatives led to the development of CPU-216, a compound that binds to the GLU344 and PHE292 residues of PGK1, effectively inhibiting its enzymatic and kinase activity. Notably, CPU-216 induces autophagy via VCP and Beclin 1 in CML-T315I cells, enhancing their responsiveness to TKIs. These discoveries propose a novel therapeutic strategy for T315I-mutant CML, underscoring the potential to develop targeted treatments that leverage the kinase functions of PGK1.
Paeoniflorin alleviates hypobaric hypoxia-triggered lung injury through targeting MEK2 to modulate ERK2-SGK1 signaling

Zhenhui Wu, Yihao Wang, Renjie Wang, Rong Gao, Shubei Li, Bodan Tu, Xiubing Yin, Maoxing Li, Wei Zhou, Huanhua Xu, Zhenfeng Wu, Zengchun Ma, Xianglin Tang, Chengrong Xiao, Yue Gao

Acta Pharmaceutica Sinica B. 2026, 16(3): 1466-1488.

Hypobaric hypoxia-induced lung injury can exacerbate the incidence of plateau pulmonary edema, but relevant pharmacologic measures are relatively limited. Here, we investigate the possible role of paeoniflorin (Pae) in hypobaric hypoxia-induced lung injury. Through in vivo and in vitro experiments, we observed that Pae significantly ameliorated hypobaric hypoxia-triggered oxidative stress, inflammatory response, mitochondrial dysfunction and ferroptosis. Using limited proteolysis-mass spectrometry (LiP-MS), molecular docking, and molecular dynamics simulations, we identified that Pae directly binds to three amino acid residues (K101, D156, and S198) of the MEK2 protein. Knockdown of MEK2 expression in vivo and in vitro abrogated the protective effect of Pae. It was also observed that Pae promotes the binding of MEK2 and ERK2 and increases the phosphorylation level of ERK2, leading to its activation. This process induced upregulation of SGK1 and the protective effect of Pae against hypobaric hypoxic lung injury was dependent on SGK1. Collectively, these findings provide pharmacological evidence that Pae activates SGK1 by targeting MEK2 and mediating MEK2-ERK2 crosstalk, highlighting Pae's potential as a promising therapeutic agent for hypoxic lung injury-related diseases.
Identification of a small-molecule targeting PLAGL2 DNA-binding domain inhibits extracellular matrix formation and enhances lenvatinib sensitivity in hepatocellular carcinoma

Acta Pharmaceutica Sinica B. 2026, 16(3): 1489-1509.

The increased stiffness of the extracellular matrix (ECM) is known to promote the progression of hepatocellular carcinoma (HCC). Currently, there are no approved therapies for targeting ECM sensors and remodelers. The objective of this study was to identify the molecular mechanisms underlying the role of Pleomorphic adenoma gene-like 2 (PLAGL2) in HCC ECM remodeling and to formulate compounds that effectively inhibit PLAGL2 transcriptional regulation. Our work revealed that PLAGL2 remodeled the ECM produced by HCC cells via an autocrine mechanism and activated HSCs via a paracrine pathway. Mechanistically, PLAGL2 functioned as a transcriptional regulator of insulin-like growth factor 2 (IGF2) and insulin-like growth factor 1 receptor (IGF1R). IGF2 enhanced ECM remodeling by HCC cells and activated HSCs through the IGF1R-PI3K-Akt signaling pathway. Furthermore, using a computer-aided drug design strategy, a novel compound, DC218, derived from the chemical evolution of cytisine, has been developed for the first time to exhibit specificity as an inhibitor of the PLAGL2 DNA binding domain. DC218 significantly degraded ECM, overcame lenvatinib resistance, and synergistically inhibited HCC. These findings provide mechanistic insight into the role of PLAGL2 in HCC ECM remodeling, as well as suggest a novel strategy for inhibiting ECM and treating HCC.
Vitamin A and its analogues modulate MUFAs metabolism to improve ferroptosis and aging by direct targeting of ACSL3

Acta Pharmaceutica Sinica B. 2026, 16(3): 1510-1529.

In our screening campaign for novel ferroptosis inhibitors, we identified that vitamin A (VA) and its metabolite all-trans retinoic acid (ATRA) exhibited potent ferroptosis-suppressing activity. Notably, through a combination of biochemical and pharmacological assays, we demonstrated that the anti-ferroptotic effects of VA and ATRA are independent of both antioxidative mechanisms and the canonical RAR/RXR signaling pathway. This conclusion was corroborated by a series of newly synthesized VA analogues. Furthermore, VA and its structural derivatives significantly alleviated ferroptosis-associated pathological phenotypes in murine models. Intriguingly, we discovered a novel function of VA and its analogues, which directly target acyl-CoA synthetase long-chain family member 3 (ACSL3) and enhance its enzymatic activity. This ACSL3-dependent mechanism increases the MUFA/PUFA ratio in phospholipids, thereby preventing lipid peroxidation. Strikingly, we further demonstrated that VA and its analogue D3 [(2E,4E,6E,8E)-N,3,7-trimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenamide] extend the lifespan of C. elegans in a manner dependent on ACSL3, highlighting the physiological relevance of this pathway in aging. Collectively, our findings unveil a previously unrecognized role for VA and its analogues in modulating lipid metabolism, thereby providing a theoretical basis for their potential application in treating ferroptosis-related diseases and possibly enhancing longevity.
Mechanistic insights into ligand selectivity in μ- and δ-opioid receptors beyond the “message-address” conceptual framework

Acta Pharmaceutica Sinica B. 2026, 16(3): 1530-1549.

Ligand selectivity between μ-opioid receptors (μ-OR) and δ-opioid receptors (δ-OR) is key for improving opioid analgesics. While the “message-address” hypothesis has been central to explaining this selectivity, we present evidence for an additional mechanism. Chimeric receptor and mutagenesis studies identify residue 2.63 in the orthosteric pocket as a key determinant of morphine's μ/δ-OR selectivity, while EM-1's selectivity involves a combination of residues at positions 2.63 and 3.29, the N-terminus, and extracellular loop 3 (ECL3). Approaches like voltage-clamp fluorometry, engineered zinc-bridge and microscale thermophoresis show that EM-1's Y¹P²W³F⁴ sequence confers over 1500-fold μ/δ-OR selectivity, driven by steric hindrance and a β-turn structure. β-Endorphin, with a more flexible sequence, binds non-selectively to both receptors. Morphine's rigid isoquinoline scaffold and broader geometry restrict it to binding through the wide ECL2-transmembrane (TM) 5 cleft, explaining its modest μ/δ-OR selectivity. These findings reveal that μ/δ-OR selectivity is driven by both “message-address” interactions and receptor-specific binding pathways, advancing opioid drug design.
Flavescensines A-L: Novel azaspiro[4.4] heterodimeric alkaloids from Sophora flavescens protect against liver injury by inhibiting DUSP2-mediated mitochondrial apoptosis

Xin Lian, Jianshuang Jiang, Yanan Yang, Ziming Feng, Xu Zhang, Xiang Yuan, Peicheng Zhang

Acta Pharmaceutica Sinica B. 2026, 16(3): 1550-1567.

By employing a targeted strategy integrating a building blocks-based molecular network (BBMN), network annotation propagation (NAP), ultraviolet spectroscopy (UV), and mass spectrometry (MS), twelve novel spirocyclic heterodimeric alkaloid flavescensines A-L (1-12) with 5/6/6/6/5 and 6/5/6/6/5 pentacyclic skeletons were isolated from Sophora flavescens. Their structures were unambiguously elucidated through comprehensive spectroscopic data, quantum chemical calculations, and single-crystal X-ray diffraction. Structurally, these compounds represent the first examples of azaspiro[4.4] alkaloids formed through the inert ring A or B of the C₁₅ matrine-type alkaloid and C₉ units. Notably, the NMR signals of C-9′ methylene can serve as diagnostic indicators to determine the absolute configuration of the spiro carbon. A plausible biosynthetic pathway involving an unusual pattern of [3 + 2] cycloaddition was proposed. The hepatoprotective activities of 1-12 were evaluated in vitro, and 10 exhibited the most significant activity. Further in vivo experiments demonstrated that 10 dramatically inhibited the APAP-induced increase in the serum ALT, AST, and LDH levels, reversed the depletion of hepatic GSH, and attenuated hepatic centrilobular necrosis and hemorrhage. Mechanistically, 10 exhibits a potential interaction with DUSP2 and inhibits its expression, thereby suppressing DUSP2-mediated mitochondrial apoptosis via PI3K/Akt/JNK pathway. This represents the first discovery of DUSP2 involving in the hepatoprotection.
The transcriptional regulatory network involved in periderm-specific tanshinones biosynthesis in Salvia miltiorrhiza root

Acta Pharmaceutica Sinica B. 2026, 16(3): 1568-1583.

Tanshinones (TAs), well-known specialized diterpenoid metabolites in Salvia plants, exhibit distinct tissue-specific production in the root periderm. However, the mechanisms regulating this accumulation pattern remain unknown. Here, we employed a multi-omics analysis strategy to uncover the transcriptional regulatory network responsible for TA biosynthesis in Salvia miltiorrhiza roots. By integrating metabolic profiling, RNA-seq, and ATAC-seq, we profile the temporo-spatial dynamics of metabolic, transcriptional, and chromatin landscapes during early root development. Our results demonstrate that TAs biosynthesis and accumulation in S. miltiorrhiza roots display spatiotemporal patterns, marked by periderm-specific accumulation and initiation exclusively at specific developmental stages, tightly coordinated with dynamic changes in chromatin accessibility and transcriptional regulation. The constructed transcriptional regulatory network driving TA biosynthesis was found to be dominated by 211 key transcription factors (TFs). Experimental validations highlighted SmERF105 as a key positive regulator of TA, activating the transcription of KSL1, CYP76AH3, and the TA transporter ABCG1 to modulate the TA production. Our study uncovers novel, high-confidence regulators and offers an effective strategy for dissecting the genetic basis of plant specialized metabolites, offering value for advancing TA metabolic engineering.

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