Acta Pharmaceutica Sinica B

Opening endothelial gap while decompressing matrix: A coordinated mechanism enhancing drug delivery in pancreatic cancer treatment

Acta Pharmaceutica Sinica B. 2026, 16(6): 3988-3989.

Development of bacterial sonosensitizer hybrid systems to enhance cancer sono-immunotherapy

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.

Engineered cell-biomimetic nanosystems for anti-inflammatory therapy: Targeting, neutralization and immunomodulation

Ruiyao Liu, Wuting Dai, Wenbo Zhou, Weilin Li, Yuan Yu

Acta Pharmaceutica Sinica B. 2026, 16(6): 3506-3539.

Inflammation is a complex and dynamic immune response triggered by tissue injury or pathogen invasion, playing a critical role in restoring tissue homeostasis. However, excessive inflammation can lead to tissue damage and exacerbate the progression of various diseases. Issues such as off-target effects and insufficient dynamic regulation pose key challenges to precise modulation of complex inflammatory processes, thereby enhancing efficacy while minimizing adverse effects. Engineered cell-biomimetic nanosystems (ECNs), including membrane-coated nanoparticles, extracellular vesicles (ECVs), and cell-nanoparticle hybrids, are highly adaptable biomimetic platforms with tunable physicochemical properties. Beyond carrier functions, ECNs are capable of actively responding to inflammation-related targets and interacting with the immune microenvironment, thereby promoting the dynamic regulation of inflammation. This review summarizes recent advances in ECNs, with an emphasis on targeting mechanisms and key strategies for inflammatory intervention. These include precise targeting of inflamed tissues, biological neutralization of toxins and overexpressed inflammatory factors to interrupt the inflammatory cascade, and immunomodulatory functions that balance immune responses to achieve activation or suppression. Physical, chemical, and biological engineering strategies for modifying cells and cell membranes for inflammation targeting are also discussed. As an emerging platform for targeted drug delivery and immune regulation, ECNs provide innovative technological approaches for inflammation therapy.

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.

The mechanisms and strategies for Alzheimer’s disease prevention: An update

Mingfeng Han, Nuoya Wang, Mengxiu Song, Chenfei Liu, Yedan Wu, Jishan Yin, Lili Jin, Wenyu Jin, Zhonggao Gao

Acta Pharmaceutica Sinica B. 2026, 16(6): 3582-3602.

Alzheimer’s disease (AD), a progressive neurodegenerative disorder, poses growing global health and socioeconomic challenges due to aging populations and limited therapeutic efficacy. Current treatments, including cholinesterase inhibitors and anti-amyloid monoclonal antibodies, can only delay disease progression without reversing pathology. Emphasizing on prevention, this review provides key updates on advancements in the pathogenesis, diagnosis, and intervention of AD highlighting preventive strategies that can target modifiable risk factors. Key findings underscore the role of managing hypertension and diabetes, optimizing trace elements, vitamins, and regular physical exercise in mitigating the risk of AD. Biomarker-based early diagnosis and emerging therapies provide further support for proactive intervention. Future challenges include the long-term validation of preventive measures and policy-driven funding for large-scale cohort studies. Prioritizing prevention through lifestyle modifications, nutritional balance, and precision medicine is pivotal to reduce the burden of AD in aging societies.

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.

Primulagenin A is a potent inverse agonist of the nuclear receptor RAR-related orphan receptor gamma (RORγ)

Acta Pharmaceutica Sinica B. 2026, 16(6): 3746-3763.

Throughout history, herbal medicines and natural products have played a crucial role as therapeutics for humans, yet their molecular mechanisms of action often remain elusive. Here, we investigate whether primulagenin A (PGA) from the traditionally used herbal substance Primula root acts via the nuclear receptor RORγ, a key regulator of pro-inflammatory Th17 cells, which are linked to autoimmune diseases like psoriasis. Full-length luciferase assays revealed a high potency (IC₅₀ = 119 nmol/L) and efficacy (Imax = 87%) of PGA as an inverse agonist of RORγ. To ensure sufficient supply, we established methods to isolate and synthesize PGA. Its binding to the human RORγ ligand binding domain was confirmed by nano differential scanning fluorimetry, and a structure-activity relationship was proposed by docking and site-directed mutagenesis. qPCR revealed PGA-mediated downregulation of RORγ target gene expression. Furthermore, PGA inhibited murine and human Th17 differentiation in a concentration-dependent manner and reduced the proportion of IL-17A-producing Th17 cells, as assessed by flow cytometry. In this work, we identify PGA as a new, potent, and efficacious inverse agonist of RORγ, with potential for modulating immune responses in inflammatory and autoimmune diseases.

VPS34 inhibition as a host-targeting anti-coronaviral strategy: Rational design of YBM with optimized pharmacokinetic parameters

Acta Pharmaceutica Sinica B. 2026, 16(6): 3784-3801.

Targeting host factors critical to the viral life cycle instead of direct viral enzyme inhibition represents a promising alternative strategy for developing broad-spectrum antivirals. Here, we identified VPS34, a key regulator of autophagosome-lysosome fusion and membrane trafficking, as a conserved host-dependency factor across coronaviruses. VPS34 gene knockdown significantly attenuates viral replication both in vitro and in vivo. Crucially, this antiviral effect remained potent against emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, demonstrating that VPS34 is a drug target resilient to viral evolution. Based on the scaffold structure of the VPS34 inhibitor SAR405, we developed YBM, a novel small-molecule inhibitor, via critical group substitutions and aliphatic chain introduction. YBM exhibited superior pharmacokinetic properties than SAR405, including enhanced bioavailability and prolonged plasma half-life. YBM shows significant in vivo efficacy against SARS-CoV-2 and HCoV-OC43. Crucially, its broad-spectrum potential is underscored by potent in vitro activity against multiple coronavirus genera (α and γ). This study established YBM as a host-targeting antiviral (HTA) that targets VPS34, offering protection against both extant and evolving coronaviruses. The evolutionarily conserved role of VPS34 in mediating coronavirus replication suggests that this host factor may become a priority therapeutic target for coronaviruses during future pandemics.

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.

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.