Acta Pharmaceutica Sinica B

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Discovery of SARS-CoV-2 PLpro inhibitors and RIPK1 inhibitors with synergistic antiviral efficacy in a mouse COVID-19 model

Acta Pharmaceutica Sinica B. 2026, 16(1): 387-405.

SARS-CoV-2 continues to propagate globally, posing non-negligible risks of severe COVID-19. Although several clinical antivirals and immunosuppressants offer crucial protection, there is a persistent need for additional therapeutic options to counter emerging viral variants and drug resistances. New strategies focusing on host targets, or simultaneously suppressing viral replication and inflammation, particularly require rigorous validation. Compared to established antiviral targets, PLpro presents an alternative actionable vulnerability in SARS-CoV-2 infection. Meanwhile, RIPK1 was pinpointed to enhance both viral replication and the resulting cytokine storm in host cells. However, inhibitors targeting PLpro or RIPK1 require further optimization for preclinical studies, and their combined efficacy in vivo has yet to be explored. Here, we report the discoveries of potent and selective PLpro inhibitors and RIPK1 inhibitors through high-throughput approaches. Our lead compounds, SHY1643 and QY1892, demonstrated synergistic and robust effects in reducing the viral loads and cytokine release syndromes in SARS-CoV-2-infected mice. These findings establish a proof-of-concept combination therapy strategy for treating severe COVID-19, and provide promising leads for the clinical drug development.
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.
Dual metabolic-inflammation modulation in MicroRNA@neutrophil-derived microvesicles achieve robust osteoarthritis therapy

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.
Oral administration of probiotic colony-like micro-nano system for immunoregulation of rheumatoid arthritis

Acta Pharmaceutica Sinica B. 2026, 16(1): 444-457.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that requires long-term pharmacological management. Melittin, a peptide derived from bee venom, has shown promising therapeutic efficacy for RA by modulating immune balance. Given the critical role of the gut in immune regulation, oral administration of melittin could have significant clinical implications. However, this approach faces substantial challenges, including degradation by gastric fluids and off-target adverse effects, which compromise its efficacy and safety. To address these limitations, we developed an innovative orally administered, gut-targeted micro-nano system (SPM/AlgL) inspired by bacterial colonies. Herein, gas-shearing microfluidics is leveraged to monodisperse sialic acid-decorated peptide nanomedicines within calcium alginate microgels. These microspheres are then coated with probiotic biofilms, leveraging their acid resistance and intestinal adhesion properties. The biofilm coating effectively protects melittin from gastric degradation and enhances its accumulation in the mesenteric lymph nodes, thereby improving its targeting ability to inflammatory sites and reducing adverse effects. By modulating the Th1/Th2 and Th17/Treg ratios in the mesenteric lymph nodes and spleen tissues, this system successfully alleviates immune responses and efficiently mitigates the progression of arthritis. Overall, this oral therapeutic strategy demonstrates significant potential for advancing the immunotherapy of RA and other systemic autoimmune diseases.
Oxygen-boosted dual-section microneedle patch for enhanced drug penetration and improved photodynamic and anti-inflammatory therapy in psoriasis

Acta Pharmaceutica Sinica B. 2026, 16(1): 458-469.

Psoriasis is a prevalent chronic inflammatory skin disorder, characterized by epidermal thickening and an inflammatory hypoxic microenvironment, which significantly hinder drug penetration through the thickened skin and limit the efficacy of photodynamic therapy (PDT). Here, we introduce a dual-section microneedle (MN) patch (termed S-PTP MN patch) to enhance the therapeutic efficacy of psoriasis treatment. The needle section contains PTP nanoparticles (NPs) loaded with triamcinolone acetonide (TA) and coated with a reactive oxygen species (ROS)-responsive layer, while the base section of the patch encapsulates sodium percarbonate (SPC) particles that serve as oxygen generators to facilitate deep penetration of the PTP NPs into inflammatory sites and improve PDT efficacy. Moreover, the PTP NPs enable sustained release of TA drug over 6 days, demonstrating potent anti-inflammatory activity. In an imiquimod-induced psoriatic mouse model, a single application of the S-PTP MN patch demonstrated superior therapeutic efficacy compared to the conventional topical TA cream, with significantly alleviated clinical symptoms, reduced epidermal thickness, and lowered inflammatory cytokine levels, highlighting the potential of the S-PTP MN patch as a clinically translatable strategy for effective psoriasis therapy.
Construction of a localized immune niche via supramolecular hydrogel vaccine to elicit durable and enhanced immunity against infectious diseases

Acta Pharmaceutica Sinica B. 2026, 16(1): 470-483.

Vaccines represent one of the most potent strategies for protecting humans from the threat of infectious diseases. Conventional vaccines elicit acquired immunity by mimicking pathogen characteristics; however, their protective efficacy is limited by inadequate spatiotemporal control of antigen delivery, resulting in suboptimal antigen exposure in lymphoid tissues and transient adaptive immune activation. Here, we developed a self-assembling peptide-based supramolecular hydrogel vaccine to establish a localized immune niche, demonstrating its remarkable efficacy in inducing durable and potent immunity against infectious diseases. We found that this in situ-formed supramolecular hydrogel vaccine serves as a reservoir for antigens and adjuvants while recruiting antigen-presenting dendritic cells (DCs) to accumulate within the scaffold. With the aid of adjuvant, the DCs exhibit enhanced antigen processing and presentation, creating an immunologically active niche that triggers robust B cell and T cell responses. Following a single vaccination, mice immunized with the hydrogel vaccine developed robust humoral immunity and sustained antibody production for 112 days, achieving potent neutralization activity. This study offers a novel approach to spatiotemporal control of vaccine responses that enables durable and enhanced immunity against infectious diseases.
Binary pyroptosis-amplified self-assembling prodrug nanomedicine enhances immunogenicity and inhibits abdominal metastasis in ovarian cancer

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.
An innovative and stable mRNA-LNP microneedle vaccine elicits humoral and multifunctional cellular immune responses

Xiaoxuan Hong, Xianfu Li, Xiaolu Han, Jinghu Lou, Yue Li, Jintao Lin, Yi Cheng, Haonan Xing, Hui Zhang, Xiwei Wang, Shuang Zhang, Nan Liu, Zengming Wang, Chunying Cui, Aiping Zheng

Acta Pharmaceutica Sinica B. 2026, 16(1): 503-521.

During the COVID-19 pandemic, the use of lipid nanoparticles (LNPs) augmented the development of mRNA vaccines. However, their ultralow-temperature storage and transportation requirements, as well as their heavy reliance on injection by professional medical staff, have limited large-scale vaccination in many developing countries. Herein, we developed a simple and widely deployable microneedle (MN) vaccine delivery system (mLNP-man-MN) for mannose-modified LNPs (mLNP-man) loaded with mRNA encoding the SARS-CoV-2 spike receptor-binding domain by utilizing three-dimensional printing and polydimethylsiloxane micro molding methods. This delivery system is composed of a dissolvable polymer mixture that was optimized for high bioactivity by screening formulations in vitro. We have demonstrated that this MN system can maintain the physicochemical properties and bioactivity of the mRNA-LNP complex even when stored at 4 °C for at least one month or at 25 °C for two weeks. Moreover, mLNP-man-MNs target the epidermis and dermis, which are rich in antigen-presenting cells, thereby eliciting effective innate immune responses and inducing robust systemic humoral responses, as well as multifunctional cellular immunity in the spleen. Importantly, the MN system induced a certain level of pulmonary T-cell responses compared to those induced by intramuscular injections, thereby providing some protection against lung invasion by the SARS-CoV-2 pseudovirus in mice.
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.

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