Acta Pharmaceutica Sinica B

Author correction to “Self-illuminating liposome-derived in situ triggerable photodynamic therapy combining radionuclide therapy for synergistic treatment of lung cancer” [Acta Pharm Sin B 15 (2025) 4973-4994]

Acta Pharmaceutica Sinica B. 2026, 16(1): 660-663.

Deep learning-based discovery of tetrahydrocarbazoles as broad-spectrum antitumor agents and click-activated strategy for targeted cancer therapy

Acta Pharmaceutica Sinica B. 2026, 16(1): 406-422.

Phenotypic screening has played an important role in discovering innovative small-molecule drugs and clinical candidates with unique molecular mechanisms of action. However, conducting cell-based high-throughput screening from vast compound libraries is extremely time-consuming and expensive. Fortunately, deep learning has provided a new paradigm for identifying compounds with specific phenotypic properties. Herein, we developed a data-driven classification-generation cascade model to discover new chemotype antitumor drugs. Through wet-lab validation, WJ0976 and WJ0909 were identified as tetrahydrocarbazole derivatives and displayed potent broad-spectrum antitumor activity as well as growth inhibitory properties against multidrug-resistant cancer cells. Furthermore, the R-(-)-WJ0909 (WJ0909B), demonstrated optimal antitumor efficacy in vitro and ex vivo patient-derived organoids (PDOs). Further investigations revealed that WJ0909B upregulates p53 expression and cause mitochondria-dependent endogenous apoptosis. Moreover, WJ0909B and the click-activated prodrug WJ0909B-TCO potently inhibited tumor growth in cell-derived xenograft models. This research highlights the significant potential of deep learning-guided approach to phenotypic drug discovery for anticancer drugs and the strategy of click-activated prodrug for targeted cancer therapy.

Engineered bacterial extracellular vesicles mediate pyroptosis to counteract m⁶A methylation-based immunosuppression after insufficient radiofrequency ablation of hepatocellular carcinoma

Acta Pharmaceutica Sinica B. 2026, 16(1): 522-538.

Insufficient radiofrequency ablation (IRFA) of hepatocellular carcinoma (HCC) leads to alterations in epigenetic properties such as N⁶-methyladenosine (m⁶A) RNA methylation in tumor cells, which creates an immune-suppressive tumor microenvironment capable of promoting residual tumor growth and recurrence and affecting the efficacy of RFA. In this study, the constructed STM-Mn@OMVs, which were produced through the rational functionalisation of bacterial-derived OMVs with Mn²⁺ ions and the methylation inhibitor STM2457, were found to effectively activate antitumor immunity. Our study shows that STM-Mn@OMVs can effectively promote dendritic cells (DCs) maturation, T cell activation, and STING pathway activation after endocytosis by cells, thus promoting immune cell infiltration. The STM-Mn@OMVs were able to promote cellular pyroptosis and synergistically activate the STING pathway. Furthermore, STM-Mn@OMVs promoted the increase of M1 macrophage phenotype in tumor-associated macrophages (TAMs) by reducing the infiltration of immunosuppressive cell populations such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), thus reversing the suppressive immune microenvironment after IRFA to some extent. Ultimately, the growth of residual tumors was inhibited. In addition, the biosafety of STM-Mn@OMVs was demonstrated in this study. Therefore, the STM-Mn@OMVs constructed in this study have great potential for application in the field of RFA and immunotherapy for HCC.

pH-Activatable engineered nanoparticle-based selective hexokinase 2 degrader provokes GSDME-dependent pyroptosis for cancer therapy

Acta Pharmaceutica Sinica B. 2026, 16(1): 539-554.

Proteolysis targeting chimeras (PROTACs) technology has been developed as an exquisite promising approach for targeted protein degradation by hijacking the cellular ubiquitin-proteasome system (UPS). However, traditional PROTACs often suffer from insufficient tumor accumulation, unfavorable membrane penetration, and always-on biological activity, limiting their antitumor performance. Herein, we report a novel pH-activatable engineered nanoparticle-based selective hexokinase 2 degrader (Nano-PROTACs) for cancer therapy. Nano-PROTACs were constructed by conjugating PEI-based PROTACs to amphiphilic nanoparticles via acid-detachable cis-aconitic anhydride (CAA) bonds. Then, Nano-PROTACs allowed PEI-based PROTACs release within the tumor acidic microenvironment, which bounded to HK-2 and recruited cereblon (CRBN) to provoke HK-2 ubiquitination for achieving HK-2 degradation via UPS. Interestingly, Nano-PROTACs specifically evoked GSDME-mediated pyroptosis to enhance cancer therapy. Thus, Nano-PROTACs effectively inhibited the growth of CT26 tumors and prevented tumor growth and lung metastasis in the orthotopic 4T1-luciferase tumor-bearing mouse model. Taken together, this study might offer a nanoparticle-based PROTACs platform for advancing selective protein of interest (POI) degradation in cancer therapy.

Binary pyroptosis-amplified self-assembling prodrug nanomedicine enhances immunogenicity and inhibits abdominal metastasis in ovarian cancer

Feng Fang, Min Su, Xue Liu, Jing Chen, Qiwen Liu, Xinran Li, Xuanbo Zhang, Yuanyuan Chen, Huijiao Fu, Zhengchai Chen, Cao Zhou, Xuzi Cai, Zhengfen Li, Zhiqiang Yu, Xuefeng Wang

Acta Pharmaceutica Sinica B. 2026, 16(1): 484-502.

Ovarian cancer remains a formidable therapeutic challenge due to its high propensity for abdominal metastasis, recurrence, and the presence of an immunosuppressive tumor microenvironment. To overcome these obstacles, we developed a self-assembled nanoplatforms (OSN) by integrating a near-infrared semiconducting polymer with an oxaliplatin(IV) prodrug. This multifunctional design enables a synergistic triple-modality therapy—photothermal therapy (PTT), photodynamic therapy (PDT), and chemotherapy—within a single nanoparticle, effectively enhancing immunogenic cell death (ICD) and systemic antitumor immunity. Upon laser irradiation, OSN generates localized hyperthermia and reactive oxygen species. These effects synergistically enhance oxaliplatin activation and tumor penetration while triggering pyroptosis through dual caspase-1-mediated and caspase-3-dependent pathways. This robust pyroptotic response amplifies the release of damage-associated molecular patterns (e.g., ATP, HMGB1) and pro-inflammatory cytokines (e.g., IL-18, IL-1β), thereby remodeling the immunosuppressive microenvironment, promoting dendritic cell maturation, and facilitating cytotoxic T-cell infiltration. In murine ovarian cancer models, OSN achieved over 90% tumor suppression, significantly outperforming monotherapies. Notably, this nanoplatform establishes long-term immune memory, effectively reducing the risk of tumor relapse. By concurrently targeting immunogenic barriers and metastatic progression through multimodal mechanisms, OSN represents a paradigm-shifting strategy with high clinical translatability for the treatment of aggressive ovarian malignancies.

Clinical insight-driven novel drug development: Multidisciplinary integration and transformative opportunities

Baohu Li, Hui Xu, Xiaoyu Shi, Chunhua Ma, Jinfei Yang, Peng Zhan

Acta Pharmaceutica Sinica B. 2026, 16(1): 651-655.

Photoimmunological hydrogel vaccine creates a supportive immune niche to promote antigen cross-presentation cascade and cancer-immunity cycle progression

Acta Pharmaceutica Sinica B. 2026, 16(1): 555-573.

Therapeutic tumor vaccines have emerged as promising weapons for inducing robust and durable antitumor immune responses, demonstrating substantial potential for cancer treatment. However, clinical efficacy is significantly hindered by tumor immunogenicity scarcity, antigen presentation deficiency, and immunosuppressive tumor microenvironment. To surmount these obstacles, we proposed an injectable photoimmunological hydrogel vaccine (CRPO/G@ALG) to improve immunotherapy outcomes through the dual mechanism of immunogenic cell death (ICD) induction and dendritic cell (DC) recruitment. The model antigen ovalbumin (OVA) and toll-like receptor 7/8 agonist resiquimod (R848) were incorporated into photothermal copper sulfide nanoparticles (CuS) to construct the nanovaccine CRPO, which was subsequently encapsulated with the granulocyte-macrophage colony-stimulating factor (GM-CSF) in sodium alginate (ALG) to form the hydrogel vaccine CRPO/G@ALG. Following peritumoral administration, CRPO/G@ALG undergoes gelation in response to physiological calcium ions, facilitating the localized retention and controlled release of payloads. Near-infrared (NIR) irradiation triggers ICD in tumor cells, generating an in situ antigen reservoir enriched with tumor-associated antigens (TAAs) to bolster tumor immunogenicity. Concurrently, GM-CSF attracts DCs to infiltrate tumor tissues, while R848 promotes DC maturation and antigen cross-presentation. These synergistic effects prolong the duration of immune stimulation and expand both the breadth and depth of antitumor immunity. In 4T1 tumor-bearing mice, CRPO/G@ALG effectively suppressed primary and distant tumor growth and markedly reduced lung metastasis. Collectively, our findings illustrate the transformative potential of integrating ICD induction, DC recruitment, and hydrogel delivery systems, offering new avenues to advance therapeutic tumor vaccine applications.

Advancing psoriasis therapy through oxygen-boosted dual-section microneedle technology

Lamyaa Albakr, Lifeng Kang

Acta Pharmaceutica Sinica B. 2026, 16(1): 658-659.

Dual metabolic-inflammation modulation in MicroRNA@neutrophil-derived microvesicles achieve robust osteoarthritis therapy

Yijun Chen, Yongbin Wang, Ruonan Yan, Yichen Liu, Yupeng Dai, Lingjing Xue, Caoyun Ju, Can Zhang

Acta Pharmaceutica Sinica B. 2026, 16(1): 423-443.

Osteoarthritis (OA) presents significant therapeutic challenges due to the irreversible cartilage loss driven by chondrocyte metabolic imbalance and a severe inflammatory microenvironment. Conventional treatments are limited by poor chondrocyte-targeting and ineffectiveness of single-target medication. Here, we develop an anti-inflammatory neutrophil-derived microvesicle (MV)-based gene therapy for OA treatment, which leverages the intrinsic cartilage-penetrating capabilities of MVs to improve the targeted delivery of microRNA-140-5p (miR140) to chondrocytes, and the synergistic effect of anti-inflammatory MVs and miR140 to dual modulate the metabolic homeostasis of chondrocytes and the inflamed microenvironment. We demonstrate that miR140@MVs not only alleviate synovial inflammation via reprogramming the phenotypes of macrophages and adsorbing inflammatory factors, but also restore normal cartilage thickness in a destabilized medial meniscus mouse model due to the rebuilt metabolic homeostasis of chondrocytes, thus gaining a remarkable therapeutic effect up to 28 days. This study provides an immuno-stimulation method for production of anti-inflammatory MVs, and puts forward a safe and effective MVs-based miRNA system for treatment of joint-related diseases.

Inhalable songorine-integrated lipid nanomedicine for targeted ARDS therapy via repairing endothelial barrier and inactivating NLRP3 inflammasome

Acta Pharmaceutica Sinica B. 2026, 16(1): 596-615.

Acute respiratory distress syndrome (ARDS) is a life-threatening disease. In the clinical management of ARDS, current treatments such as glucocorticoids and protease inhibitors encounter significant challenges due to their high toxicity, limited administration routes, or poor targeting. These limitations highlight the urgent need for innovative therapeutic strategies. Songorine (Son), a compound derived from the herb Aconitum carmichaelii Debeaux, possesses good antioxidant and anti-inflammatory properties, exhibiting great potential for treating ARDS. However, its clinical application is partially constrained by low aqueous solubility and uncertain efficacy for ARDS. In this study, we developed a lung-targeted lipid nanomedicine by encapsulating Son in dipalmitoyl phosphatidylcholine (DPPC) liposomes (Son@liposome, Son-lipo). In a lipopolysaccharide-induced ARDS mouse model, we demonstrated that Son-lipo effectively targeted inflamed lung tissues with commendable biocompatibility. Further, Son-lipo significantly alleviated multiple ARDS phenotypes such as endothelial barrier damage, lung edema, pulmonary dysfunction, and alveolar lesion, which involved uncontrolled inflammation, oxidative stress, and cell apoptosis. RNA sequencing and Western blotting analyses revealed that Son-lipo inhibited the activation of the TLR4/NF-κB/NLRP3 pathway responsible for ARDS. In conclusion, our study successfully developed an inhalable lipid-nanomedicine (Son-lipo) as a novel therapeutic strategy for ARDS. It elucidates the formulation's ability to mitigate ARDS by repairing the endothelial barrier and reversing the inflammatory microenvironment, thereby providing a promising candidate drug for improving clinical management of ARDS.