Acta Pharmaceutica Sinica B

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A neurotensin receptor type 1-derived pepducin acts as a biased allosteric modulator to regulate target receptor function

Acta Pharmaceutica Sinica B. 2026, 16(4): 2396-2419.

Pepducins are synthetic membrane-tethered lipopeptides designed to allosterically modulate G protein-coupled receptor (GPCR) signaling. Here, we characterize a series of pepducins targeting the neurotensin receptor type 1 (NTSR1), revealing their complex and multifaceted modulation properties. Using BRET-based biosensors, we show that PP-001, a pepducin derived from NTSR1’s first intracellular loop, preferentially activates G protein over β-arrestin signaling while inhibiting NT binding, NT-induced β-arrestin recruitment, and NTSR1 internalization, thereby acting as biased allosteric agonist and negative allosteric modulator. PP-001 also promotes the formation of both homo- and heteromeric multi-receptor complexes. In vivo, PP-001 elicits potent, sustained hypotensive effects, reversible by the NTSR1 antagonist SR48692. Although the precise mechanism of pepducin-receptor interaction remains unclear, we identify a critical N-terminal RKK motif for PP-001’s biological activity. Finally, thermodenaturation assays using purified NTSR1, combined with mutagenesis and molecular docking, provide evidence for the role of the receptor’s H8 domain in direct pepducin interaction. Together, these findings highlight pepducins as versatile modulators of GPCR function and as valuable pharmacological tools for GPCR-targeted drug development.
From target specificity to metabolic efficiency: Design and optimization of etomidate analogues for potential improvement in postoperative outcomes

Acta Pharmaceutica Sinica B. 2026, 16(4): 2420-2443.

While transient perioperative side effects of intravenous anesthetics are often tolerated, the persistent postoperative sequelae resulting from drug accumulation pose a critical threat to patient safety. Etomidate, introduced in the 1970s, remains favored for its minimal hemodynamic impact but is severely limited by sustained adrenal suppression, leading to higher mortality and poorer outcomes in critically ill patients. To address these challenges, we reframed our strategy from solely optimizing receptor specificity to enhancing metabolic efficiency, thereby reducing prolonged postoperative exposure and mitigating sustained adverse effects. Using a deep-learning based molecule optimization algorithm, we identified metabolically favorable lead compounds and synthesized 31 novel imidazole-based etomidate derivatives. Among these, ETO-4 emerged as the most promising candidate, retaining potent anesthetic activity while accelerating metabolic clearance and significantly diminishing adrenal suppression. Plasma cortisol assays confirmed the effect of ETO-4 on adrenal function is greatly reduced. These findings underscore a paradigm shift in anesthetic drug design, demonstrating that prioritizing enhanced metabolic profiles can yield safer, more effective agents that improve postoperative outcomes.
Generative active learning guided discovery of a tobramycin and ciprofloxacin adjuvant against multidrug-resistant Pseudomonas aeruginosa infections

Acta Pharmaceutica Sinica B. 2026, 16(4): 2444-2473.

Biofilm-mediated resistance in multidrug-resistant (MDR) Pseudomonas aeruginosa infections severely compromise antibiotic efficacy in clinical applications. Antibacterial adjuvants represent a promising strategy to restore antibiotic sensitivity and reduce therapeutic dosages. To identify new antibacterial adjuvants with unique structure and mechanism, we established a generative active learning workflow integrating an in-house compound repository of 725 biofilm inhibitors and a library of potential antibiofilm targets. The most potent compound STY17 was identified with sub-micromolar antibiofilm activity (IC₅₀ = 0.29 ± 0.01 μmol/L). In clinically isolated MDR Pseudomonas aeruginosa, STY17 significantly inhibited biofilm formation, potently synergized with tobramycin and ciprofloxacin, and suppressed the resistance development of these antibiotics. Furthermore, mechanistic studies indicated that STY17 inhibited succinate dehydrogenase to disrupt biofilm formation. In vivo, STY17 significantly enhanced the antibacterial activity of tobramycin and ciprofloxacin in Galleria mellonella and the mouse wound infection model with favorable safety profiles. These findings validated the utility of machine learning to discover novel antibacterial adjuvants, revealing STY17 as a promising candidate for antibacterial adjuvants against MDR Pseudomonas aeruginosa infections.
An oral immune enhancer with excellent biocompatibility for effectively strengthening body’s immunity and treating cancer

Anqi Xie, Lei Feng, Yaping Shao, Yiqun Wan, Ying Zhang, Zheyi Liu, Haihua Ji, Hao Wan

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.
Engineered apoptotic vesicle mimetics with tunable “eat-me” signaling precisely regulate tumor-associated macrophages for potentiating cancer immunotherapy

Acta Pharmaceutica Sinica B. 2026, 16(4): 2498-2512.

Repolarizing immunosuppressive M2-phenotype tumor-associated macrophages (TAMs) and blocking the CD47/SIRPα axis are promising strategies to enhance cancer immunotherapy. However, non-selective disruption of macrophage phenotypic balance and CD47/SIRPα signaling can lead to immune-related side effects. To address this, we develop a smart biomimetic nanoparticle (PARM) loaded with R848 and manganese ions (Mn²⁺). PARM is coated with an apoptotic vesicle membrane and a pH-sensitive PEG corona, enabling targeted delivery to TAMs in the acidic tumor microenvironment (TME). The PEG corona protects the nanoparticle from uptake during circulation and sheds in the TME, exposing the apoptotic vesicle membrane. This triggers specific recognition and uptake by TAMs via the “eat-me” signal. R848 and Mn²⁺ repolarize TAMs into a pro-inflammatory phenotype, while the activation of cGAS-STING pathway by Mn²⁺ reduces SIRPα expression and enhances TAM phagocytosis. In vivo studies demonstrate that PARM remodels the immunosuppressive TME by repolarizing TAMs and promoting CD8⁺ T cell infiltration. This leads to significant inhibition of tumor growth and metastasis. These findings highlight the multifaceted role of the cGAS-STING pathway in TAM modulation and present a novel strategy for enhancing macrophage-based cancer immunotherapy.
In situ rewiring TAMs as annihilators by “Spark-relay” nanoinitiator with flexible reactant ratio for amplifying solid tumor immunotherapy

Xinping Luo, Yingmeng Jiang, Qing Zhang, Jie Yu, Chenxi Zhou, Zhanwei Zhou, Minjie Sun

Acta Pharmaceutica Sinica B. 2026, 16(4): 2513-2526.

Tailoring tumor-associated macrophages (TAMs) into the tumoricidal phenotype represents a high-profile strategy for tumor immunotherapy. However, the existing TAMs repolarization strategies are restricted by hostile microenvironmental stress and metabolic compensation, leading to limited anti-tumor phenotype sustainability. Herein, a “Spark-Relay” nanoinitiator (SRN) with flexible S/R reactant ratio was meticulously designed for rewiring TAMs as tumoricidal bioreactor and precisely overcome metabolic compensation. Briefly, SRN reshaped TAMs in situ relying on tissue tropism of macrophage membrane, firstly upregulating their reactive oxygen species (ROS) production via burst release of Spark element and initially shifting the TAMs into the anti-tumoral phenotype, subsequently elevating NO production by releasing Relay element, which is converted to NO via reaction with ROS and iNOS, leading to the generation of additional ROS and creating a positive feedback loop, thereby strengthening the metabolic rewiring of TAMs from passively defensive oxidative phosphorylation to positively offensive glycolysis, which significantly enhanced the antitumoral activity of TAMs and shrunk tumor immunosuppressive microenvironment, emerging as 5.5-fold increase of tumor-suppressive/supportive ratio (TSSR) of TAMs, 4.0-fold elevation of CD8⁺ T cell infiltration, contributing to a satisfactory tumoricidal efficacy and providing a cascade amplification mode for TAMs-based cancer therapeutics.
Targeted intestinal barrier repair via probiotic-derived engineered outer membrane vesicles: A 3A1M strategy with antioxidant, anti-inflammatory, anti-ferroptotic, and microbiome modulation effects

Acta Pharmaceutica Sinica B. 2026, 16(4): 2527-2552.

Intestinal barrier disruption, driven by oxidative stress, ferroptosis, immune imbalance, and gut microbiota dysbiosis, plays a crucial role in inflammatory bowel disease (IBD) pathogenesis. Current treatments are often ineffective and cause side effects, emphasizing the need for novel therapies. Here, we have developed an engineered probiotic-derived outer membrane vesicle (OMV), GDO@CM, combining antioxidant gallic acid (GA) and anti-inflammatory H₂S for targeted intestinal barrier repair. Constructed from Escherichia coli Nissle 1917 (EcN)-derived OMVs, GA and diallyl trisulfide (DATS) are incorporated into the hydrophilic inner cavity and lipid bilayer, respectively, while mannose-decorated chitosan (CM) is electrostatically attached to the OMVs surface, enhancing stability and enabling targeted delivery to damaged colonic lesions. GDO@CM efficiently enters activated immune cells and epithelial cells, where GA scavenges reactive oxygen species and inhibits ferroptosis, while H₂S amplifies anti-inflammatory effects. OMVs further synergize with GA and DATS to suppress pathogenic bacteria. These combined actions facilitate effective barrier repair and alleviate IBD symptoms. Single-cell RNA sequencing reveals that GDO@CM reduces inflammation, increases the proportion of reparative M2 macrophages and intestinal stem cells, and promotes epithelial cell proliferation via the APP/CD74 axis. Our findings establish GDO@CM as a promising multi-target therapeutic for IBD, offering a novel strategy for intestinal barrier restoration.
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.
A spatiotemporal selective bioinspired hybrid system engineered for preventing post-thrombolysis recurrence by inhibiting the ferroptosis pathway and reprogramming macrophages

Acta Pharmaceutica Sinica B. 2026, 16(4): 2570-2586.

Cardiovascular diseases induced by arterial thrombosis, such as myocardial infarction and ischemic stroke, have gradually emerged as critical threats to human life and health. Sequentially targeted delivery systems are highly desired to be developed to improve the delivery of thrombolytics and anti-inflammatory medications to the site of the thrombus, respectively, to pursue a maximized combinational effect. Herein, we developed a probiotic-platelet hybrid vesicle-targeted drug delivery system (Fer-1@PLevs-C&U) to achieve sequential anti-thrombolytic delivery against thrombus and prevent its recurrence. The hybrid vesicles (PLevs) were prepared by mixing platelet membrane with Lactobacillus plantarum-derived bacterial extracellular vesicles (Levs) and further decorated with DSPE-PEG₂₀₀₀-CREKA, achieving “point-to-point” multi-covalent targeting of thrombus components. After targeted localization to the arterial thrombotic site, Fer-1@PLevs-C&U gradually releases the thrombolytic drug urokinase-type plasminogen activator (UPA) and Ferroptosis inhibitor (Fer-1) to facilitate thrombus dissolution and regulate the inflammatory microenvironment. By enhancing the eNOS expression and reducing the secretion of inflammatory factors TNF-α and IL-6, Fer-1@PLevs-C&U significantly reduced the inflammatory microenvironment and inhibited recurrent thrombus. Therefore, Fer-1@PLevs-C&U constitutes a novel biomimetic drug delivery platform with promising therapeutic potential and practical applicability.
Identification of HMGB1 as a target of 3-O-benzoyl-20-deoxyingenol in NSCLC therapy using integrated ABPP and SIP

Acta Pharmaceutica Sinica B. 2026, 16(4): 2587-2592.

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