Acta Pharmaceutica Sinica B

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Structural characterization of emulsion-type cataplasms with cross-linked networks and systematic establishment of structural parameters

Acta Pharmaceutica Sinica B. 2026, 16(6): 3828-3845.

Compared with conventional cataplasms, those incorporating a cross-linked network structure significantly enhance their mechanical strength and cohesion, endowing them with good formability and adhesion properties, solving problems such as cold flow and slippage, thereby greatly increasing the convenience of use. However, systematic studies investigating the structural profiling of cross-linked networks in cataplasms remain scarce, limiting a comprehensive understanding of their functional significance. Therefore, we developed a systematic methodology to characterize emulsion-type cataplasms (as a model formulation) with cross-linked network structures, classifying their key structural parameters into four levels. The primary structures defined formability and adhesion, ensuring intact and durable skin adhesion. The secondary structure was intermediates formed by the drug and oily components. The tertiary structure was a dynamic structure, evaluating the quality changes of cataplasms during processes such as crosslinking and storage. The quaternary structure was a molecular structure, representing the mechanism by which the cross-linked network structure was formed. The factors influencing structural parameters and the laws between the intrinsic structures were investigated. Furthermore, we established threshold values for the primary structures, indicating when cataplasms possess optimal formability. This study offers new insights for cataplasm design and provides valuable references for industrial development.
Soft cell-derived hybrid microparticles with platelet decoys for enhanced cancer chemotherapy

Nana Bie, Shiyu Li, Kaili Sun, Jianye Li, Xin Li, Xiaojuan Zhang, Muzi Tian, Zixiang Xie, Yixi Xiao, Yujie Zhang, Zixi Wang, Yizhou Huang, Yinmei Zhu, Xiangliang Yang, Lu Gan, Tuying Yong

Acta Pharmaceutica Sinica B. 2026, 16(6): 3846-3860.

Platelets play a critical role in tumor development, metastasis and chemoresistance, making the effective killing of tumor cells and simultaneously targeted disruption of platelet functions essential for improving cancer treatment outcomes, especially in post-surgical malignant tumor patients. Here, we develop soft hybrid microparticles (3D-PMPs) by fusing tumor-repopulating cell-derived microparticles with inactivated platelet membranes to deliver the anticancer agent doxorubicin (DOX@3D-PMPs). Leveraging their unique softness, DOX@3D-PMPs demonstrate superior tumor accumulation, deep tumor penetration, and enhanced internalization into tumor cells, leading to efficient tumor cell killing. Additionally, 3D-PMPs function as highly targeted platelet decoys to disrupt platelet-tumor cell interaction and reduce platelet-driven tumor proliferation and metastasis. Mechanistically, Toll-like receptor 4 (TLR-4) presented on 3D-PMPs is responsible for their platelet decoy function. DOX@3D-PMPs demonstrate significantly enhanced therapeutic efficacy in both orthotopic 4T1 breast tumors and post-surgical orthotopic 4T1 breast tumors. This work offers a novel and effective approach to enhance the therapeutic outcomes in cancer treatment, particularly in post-surgical settings.
Microthrombi targeted nano-micelle synchronizing endothelial gap opening and matrix decompression for augmenting drug perfusion within pancreatic cancer

Acta Pharmaceutica Sinica B. 2026, 16(6): 3861-3875.

Local inhibition of the “patching” function of tumor-associated platelets against neutrophil infiltration-caused vascular breaches has been used as an “enhanced permeability and retention (EPR) amplification” strategy. Nevertheless, the vascular leakage-resulted elevation of interstitial fluid pressure (IFP) could impact tumoral perfusion and convection of nanodrugs. Especially for hypoperfused and desmoplastic pancreatic ductal adenocarcinoma (PDAC), solely relying on vascular destruction would predictably diminish tumoral drug perfusion. According to multi-thrombosis formation in PDAC, a microthrombi and matrix co-targeted dasatinib (DAS) nano-micelle (CPHD/DAS) synchronizing endothelial gap opening and matrix decompression was constructed for sustained augmentation of drug perfusion within PDAC. CPHD/DAS was composed of CREKA peptide-modified hyaluronic acid-deoxycholate conjugates co-assembled with DAS. In vitro and in vivo results demonstrated CPHD/DAS not only retarded tumor-associated platelet activation to enhance vascular permeability and expose subvascular matrix, but also inhibited pancreatic stellate cell activation to alleviate stroma barrier. Thus, the matrix decompression resisted IFP elevation caused by endothelial gap opening, facilitating sustained up-regulation of functional vessels. Based on superior tumor accumulation and penetration, CPHD/DAS exhibited favorable potency in Panc02 tumor model. This study provides a paradigm to improve the efficiency and application scope of “EPR amplification” strategy in antitumor therapy.
A lymph node-targeted cell-nanoadjuvant conjugate enhances dendritic cell-T cell crosstalk for cancer immunotherapy

Acta Pharmaceutica Sinica B. 2026, 16(6): 3876-3891.

Dendritic cell (DC) vaccines represent a promising immunotherapeutic strategy by eliciting potent anti-tumor immunity. However, their clinical application remains limited due to poor lymph node (LN) targeting and inadequate T cell activation. Here, we developed an LN-targeted cell-nanoadjuvant conjugate by click-chemistry conjugation of anti-PD-1 antibodies (αPD-1) and Resiquimod (R848) liposomes to DC vaccines (DCVs) (DCV-αPD-1/Lipo) to enhance DC-T cell crosstalk for cancer immunotherapy. DCV-αPD-1/Lipo maintains higher co-stimulatory molecule expression and antigen presentation with enhanced LN targeting efficiency than conventional DC vaccines. The surface-conjugated αPD-1 increases DC-T cell adhesion by 4.97-fold while amplifying the IFN-γ/IL-12 positive feedback loop, thereby potentiating T cell activity and augmenting effector T cells and other immune cells mediated anti-tumor efficacy. This multifunctional integration of adaptive DC therapy, nanoadjuvants and checkpoint blockade establishes an effective approach for next-generation DC therapy.
Interleukin 12-tethered nano-aluminum adjuvant orchestrates environmental immunomodulation to empower cytotoxic T cells against solid tumors

Acta Pharmaceutica Sinica B. 2026, 16(6): 3892-3906.

The immunosuppressive tumor microenvironment (TME) profoundly limits the therapeutic efficacy of CD8⁺ T cells in solid tumors. While cytokine therapies have shown promise in reactivating CD8⁺ T cells, they fail to address the common suppressive environmental attributes (e.g., acidosis and Mg²⁺ deficiency) of solid tumors. Here, we report an innovative CD8⁺ T cell dual-functional modulator, interleukin-12-tethered nano-aluminum adjuvant (IL12@NAM), which counteracts the acidic TME to relieve acidosis and concurrently releases Mg²⁺ and IL12. Locally released Mg²⁺ and IL12 synergize in T cell infiltration and activation by promoting the phosphorylation of focal adhesion kinase and extracellular signal-regulated kinase 1/2, and enhance CD8⁺ T cell activation and functions via the Ca²⁺-nuclear factor of activated T cells 2 pathway. Furthermore, dual-functional IL12@NAM mitigates CD8⁺ T cell exhaustion by reducing PD1 and LAG3 expression and effectively increases the differentiation towards T helper 1 cells while decreasing regulatory T cells, creating a more favorable immune network for enhanced CD8⁺ T cell-mediated anti-tumor immunity. As a result, IL12@NAM has demonstrated potent therapeutic efficacy against advanced melanoma and breast cancer, and remarkably empowered adoptive T therapy of solid tumors. This study provides a paradigm for empowering cytotoxic T cells by reactivating and creating a sustainable immunoresponsive environment, offering a potential adjuvant strategy to enhance solid tumor therapy.
RAD51-targeting small molecule degrader sensitizes BRCA-proficient prostate cancer cells to PARP inhibitors via synthetic lethality

Acta Pharmaceutica Sinica B. 2026, 16(6): 3907-3919.

Poly (ADP-ribose) polymerase (PARP) inhibitors though effective in patients with homologous recombination (HR)-deficient tumors, a large population of patients remain unresponsive, primarily due to either the absence of HR-related mutation or the restoration of HR functionality. RAD51, a critical protein in HR repair signaling that ensures precise DNA lesion repair, represents a promising therapeutic target. Inspired by the clinical success of PARP inhibitors in treating BRCA1/2-mutant cancers and leveraging the potential of proteolysis-targeting chimeras (PROTAC) technology—a method that exploits the cell's protein degradation machinery to eliminate disease-associated proteins, we generated a small-molecule PROTAC G73. This compound degrades RAD51 in a concentration- and time-dependent manner, effectively mimicking the HR-deficient phenotype by impairing DNA double-strand break (DSB) repair. Furthermore, G73-mediated RAD51 degradation synergizes with the PARP inhibitor olaparib, inducing synthetic lethality and re-sensitizing olaparib-resistant cancers to PARP inhibition. This fully small-molecule-based strategy presents a compelling strategy to overcome resistance to PARP inhibitors, expanding their therapeutic potential beyond patients with HR-deficient tumors.
Development of bacterial sonosensitizer hybrid systems to enhance cancer sono-immunotherapy

Haiyan Guo, Yuhan Li, Xue Chen, Xiuru Ji, Zeyang Liu, Hongjing Jiang, Han Wang, Dalong Ni

Acta Pharmaceutica Sinica B. 2026, 16(6): 3920-3933.

Microorganisms can activate anti-tumor immune responses via the innate immune system. However, this immune effect lacks specificity, and prolonged stimulation by live bacterial colonization may lead to immune tolerance. Sonodynamic therapy triggers cellular death and lysis, fully activating the antigen presentation process by providing heterologous DNA and tumor antigen in situ. Herein, to enhance the immunological effect facilitated by ultrasonic treatment, a manganese-containing porphyrin-based metal-organic framework (Mn-MOF) was modified as an acoustic sensitizer on the surface of Escherichia coli to form bacterial sonosensitizer hybrid systems (HA@Mn-MOF@E). Importantly, HA@Mn-MOF@E was able to target and colonize 4T1 tumors due to the anoxic tendency of anaerobes. The ultrasound-induced bacterial and tumor cell death and released manganese could activate macrophages and dendritic cells (DCs) through the activation of the cGAS-STING pathway, which increased the proportion of CD3⁺ T cells and M1/M2 ratio within the tumor, as well as CD8⁺ effector T cells and CD86⁺ DCs in lymph nodes. By sono-sensitized immunotherapy, HA@Mn-MOF@E was demonstrated to inhibit orthotopic 4T1 tumor progression and induce tumor necrosis effectively. Such a designed bacterial sonosensitizer hybrid system offered the possibility of using sonodynamic assistance to sensitize live microorganisms-induced immunotherapy, with thorough activation of the antigen presentation in the tumor.
Astragalus-derived nano-agonist potentiates chemotherapy by reducing tumor-suppressive macrophages

Xuan Han, Yongbing Yang, Qiwen Lu, Zihan Zhang, Chengcheng Zhang, Xi Wang, Yueyi Huang, Hurong Shen, Qichen Zhan, Jing Chen, Peng Cao

Acta Pharmaceutica Sinica B. 2026, 16(6): 3934-3952.

Platinum-based chemotherapy only achieves a short-term success in the treatment of triple-negative breast cancer (TNBC), which is attributed to immunosuppressive macrophages post-chemotherapy. Herein, inspired by the plant immune defense mechanism, we demonstrate that edible astragalus-derived exosome-like nanoparticles (ADNPs) exhibit conspicuous efficacy in reprogramming M1-like tumor-associated macrophages (TAMs) through the activation of TLR2 signaling. The docking between released formononetin and TLR2 plays a key role during the cell internalization process. As a result, ADNPs in combination with Cisplatin (termed ADNP-Cis) greatly inhibit TNBC murine tumor progression and metastasis. Besides, ADNPs alleviate the peripheral blood toxicity caused by cisplatin treatment, and show lower toxicity compared with other TLR2 agonists previously reported. Taken together, this safe and robust ADNP-Cis therapy offers fresh insights into the management of TNBC chemotherapy.
Structural insights into pterocarpan reductases unveil a universal ring-opening mechanism in plant biosynthesis of 4-(furan-2-yl) phenol derivatives

Acta Pharmaceutica Sinica B. 2026, 16(6): 3953-3962.

Pterocarpans and isoflavans are important phytoalexins, and demonstrate significant benefits to human health. Pterocarpan reductases (PTRs) catalyze the conversion of pterocarpans to isoflavans, while the catalytic mechanism remains unknown. Herein, we report six PTRs (GuPTR1-6) from Glycyrrhiza uralensis, together with the first PTR crystal structure (GuPTR1/(-)-medicarpin/NADP⁺, 1.8 Å). Structural analysis and mutagenesis reveal that a lysine-mediated deprotonation of the 7-OH group triggers C‒O bond cleavage of pterocarpans in the furan ring-opening reactions. This mechanism also applies to similar ring-opening enzymatic reactions. Through ancestral sequence reconstruction, we obtained a multifunctional reductase N0, which could accept different types of 4-(furan-2-yl) phenol derivatives as substrates. This study not only unveils the catalytic mechanisms of PTRs, but also provides a powerful enzymatic tool for the synthesis of bioactive isoflavans.
Discovery and mutasynthetic optimization of ansatrienin B: A new broad-spectrum inhibitor against RNA viruses

Acta Pharmaceutica Sinica B. 2026, 16(6): 3963-3984.

RNA viruses, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), flaviviruses, and alphaviruses, represent a major source of emerging human infectious diseases. They pose a persistent threat to public health; however, few therapeutic options are available for severe infections. Through a natural product screening campaign, we identified ansatrienin B as a broad-spectrum inhibitor of multiple RNA viruses, including SARS-CoV-2, flaviviruses (e.g., YFV, WNV, DENV), and alphaviruses (e.g., CHIKV). Time-of-drug-addition assays indicated that ansatrienin B acts at both the early (entry) and intermediate (replication) stages of the viral life cycle. Surface plasmon resonance (SPR) and molecular docking studies validated a direct interaction between ansatrienin B and the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 and WNV. Combined RNA pull-down and RdRp enzymatic activity assays (in gel, solution, and cellular forms) further demonstrated that ansatrienin B disrupts both the binding of RdRp to viral RNA and its enzymatic activity. In vivo, ansatrienin B showed significant efficacy in mouse models infected with SARS-CoV-2 or WNV infection. To facilitate screening and elucidate the structure-activity relationship (SAR), we generated a focused ansatrienin library via a mutasynthetic approach. Supplementation of four 3,5-AHBA analogs into a △mycB1-B4 mutant strain of Streptomyces flaveolus yielded 30 novel ansatrienin derivatives. Evaluation of anti-SARS-CoV-2 activity identified four analogs with enhanced potency, enabling the establishment of a preliminary SAR. Collectively, these findings establish ansatrienin B as a novel inhibitor targeting RdRp and provide a foundation for the development alternative broad-spectrum antiviral agents.

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