Acta Pharmaceutica Sinica B

Radiation-induced nuclear translocation of NPRL2 hijacks E3 ubiquitin ligases to enhance DNA repair via the AMPK/WDR24 axis, contributing to CRC radioresistance

Xuecen Wang, Yuxuan Zhao, Xingli Yang, Tingyu Liu, Weilin Zhou, Shaoqing Niu, Meng Jin, Yong Chen, Ran-yi Liu, Yong Bao, Xin Yue

Acta Pharmaceutica Sinica B. 2026, 16(1): 252-269.

Radiotherapy resistance remains a major clinical challenge in colorectal cancer (CRC) treatment. Our study reveals that the regulation of nuclear E3 ubiquitin ligase maintains K48-ubiquitin levels that correlate with CRC radiotherapy sensitivity. We identify NPRL2 as the central mediator of this process. Following radiation, NPRL2 rapidly translocates to the nucleus, where it directly binds to the catalytic domains of key E3 ubiquitin ligases, including HERC2 and RNF8, and functionally inactivates them. This NPRL2-mediated inhibition of E3 ligase activity prevents the degradation of critical DNA repair proteins. Importantly, clinical analyses demonstrate that nuclear NPRL2 plays a role in sustaining radioresistance. Mechanistic investigations reveal that radiation-induced AMPK activation initiates this process by phosphorylating WDR24, which promotes NPRL2 dissociation from the GATOR1 complex and facilitates its nuclear translocation. Therapeutic targeting through AMPK inhibition effectively blocks NPRL2 nuclear accumulation, leading to impaired DNA damage repair and significant radiosensitization of CRC cells in both in vitro and in vivo models. These findings not only elucidate the AMPK/WDR24/NPRL2 signaling axis as a fundamental regulator of DNA repair machinery in CRC, but also provide compelling evidence for its potential as a novel therapeutic target to overcome radioresistance and improve radiotherapy efficacy in CRC patients.

The progress and perspective of nanomedicine in modulating the tumor immune microenvironment

Nan Lin, Keqin Tan, Yuhao Wei, Songtao Xie, Jiaming Liu, Xuelei Ma

Acta Pharmaceutica Sinica B. 2026, 16(1): 137-168.

The widespread application of nanomedicine in oncology is reshaping cancer treatment paradigms. Using the precise targeting mechanisms and the rapid advancements in nanoscale materials, nanomedicine is driving progress in cancer therapy, particularly within the complex landscape of the tumor immune microenvironment (TIM). This review provides a comprehensive overview of recent studies elucidating the critical role of nanomedicine in modulating the TIM, augmenting the efficacy of immunotherapies, and overcoming therapeutic resistance. Emphasis is placed on the significance of targeted drug delivery systems, innovative nanoscale vaccines, and strategies for reprogramming immunosuppressive cells. Furthermore, the review explores the clinical applicability and prospects of personalized nanomedicine, highlighting its increasingly prominent role in tailored cancer therapeutics.

DHL-11, a novel prieurianin-type limonoid isolated from Munronia henryi, targeting IMPDH2 to inhibit triple-negative breast cancer

Yu Zhu, Zhibi Zhang, Xueqin Dai, Wenjing Liu, Jian Sun, Jialing Liu, Yuxin Zhao, Wenlong Ren, Chenglong Pan, Zhongmei Zhou, Ying Yan, Longlong Zhang, Ceshi Chen

Acta Pharmaceutica Sinica B. 2026, 16(1): 287-304.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterized by the poorest prognosis, and poses a significant threat to women's health. In this study, we identified two novel prieurianin-type limonoids extracted from Munronia henryi, one of which, named DHL-11, exhibited antitumor activity against TNBC cells. DHL-11 suppressed cell proliferation and migration, induced G2/M cell cycle arrest and apoptosis, and effectively increased the accumulation of reactive oxygen species (ROS) and cellular DNA damage in TNBC cells. Mechanistically, we found that DHL-11 binds to the non-catalytic pocket of IMPDH2 and disrupts the interaction between IMPDH2 and FANCI, leading to the degradation of the IMPDH2 protein. The decrease of IMPDH2 protein reduced guanine synthesis, increased ROS levels, and induced DNA damage. DHL-11 significantly inhibited the growth of breast cancer patient-derived organoids with high IMPDH2 expression. Furthermore, DHL-11 inhibited the growth and metastasis of TNBC xenografts in vivo with favorable biosafety profiles. Our findings highlight the potential of DHL-11 as a novel IMPDH2 degrader for the treatment of IMPDH2-positive TNBC.

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.

Concerns and challenges in clinics-guided nanovaccines design and applications

Acta Pharmaceutica Sinica B. 2026, 16(1): 198-230.

Vaccines play a crucial role in the prevention and treatment of multiple diseases. Given the constraints of conventional vaccines, the development of nanovaccines, characterized by their superior design flexibility and controllability, has emerged as a compelling alternative. By utilizing nanotechnology, nanovaccines optimize the targeted delivery of antigens and adjuvants, augment antigen presentation, and facilitate precise modulation of immune cell responses, thereby exhibiting substantial potential for both preventive and therapeutic applications across a range of diseases. However, research on nanovaccines is currently stalled at the preclinical stage, with numerous challenges and shortcomings hindering their clinical translation. Herein, we discuss various design concepts and strategies for nanovaccines, along with their biomedical applications, with an emphasis on the challenges, future directions, and strategies of their clinical translation. We specifically highlight the core principles that need to be achieved in the preclinical development of nanovaccines, aiming to explore strategies to overcome existing challenges and promote their clinical application.

Omics-based large language models: A new engine for drug discovery innovation

Acta Pharmaceutica Sinica B. 2026, 16(1): 122-136.

Traditional drug discovery suffers from low efficiency and high attrition rates, largely due to the complexity and heterogeneity of human diseases. Omics technologies offer a systems-level perspective for uncovering disease mechanisms and identifying therapeutic targets, but present challenges such as high dimensionality, noise, and heterogeneity. Large language models (LLMs), originally developed for natural language processing, are emerging as powerful tools to address these issues by capturing complex patterns and inferring missing information from large, noisy datasets. We present a three-part framework: (1) Analyzing how LLM architectures and learning paradigms handle challenges specific to genomics, transcriptomics, and proteomics data; (2) Detailing LLM applications in key areas: uncovering disease mechanisms, identifying drug targets, predicting drug response, and simulating cellular behavior; (3) Discussing how insights from omics-integrated LLMs can inform the development of drugs targeting specific pathways, moving beyond single targets towards strategies grounded in underlying disease biology. This framework provides both conceptual insights and practical guidance for leveraging LLMs in omics-driven drug discovery and development.

Chinese medicine and intermittent fasting integration therapy attenuate diabetic vascular calcification via miR21-5p/Tpm1-mediated osteogenic differentiation of VSMCs

Acta Pharmaceutica Sinica B. 2026, 16(1): 352-370.

Vascular calcification (VC) is a marker of substantial vascular damage in patients with diabetes and has been recognized as a predictor of cardiovascular events and all-cause mortality. To date, no effective therapeutic strategy has been formulated for the management of VC. In this study, we integrated the treatment regimen of the Danlian-Tongmai (DLTM) formula, a traditional Chinese medicine (TCM) with anti-diabetic VC (anti-DVC) effects with intermittent fasting (IF), and established the Chinese medicine and intermittent fasting integration therapy (CMIT). CMIT synergistically enhanced the regulation of calcium-phosphorus homeostasis and vascular repair, and demonstrated significantly greater efficacy than DLTM or IF monotherapy in inhibiting calcium deposition and osteogenic differentiation both in vivo and in vitro. Transcriptomic sequencing revealed that the miR21-5p/Tpm1 axis mediated the anti-calcification effect of CMIT. MiR21-5p promoted the overproliferation, migration, and osteogenic differentiation of vascular smooth muscle cells (VSMC) by negatively regulating Tpm1, while CMIT inhibited such processes. In conclusion, this study demonstrated that CMIT inhibited the osteogenic differentiation of VSMC and restored its contractile phenotype by inhibiting the activation of the miR21-5p/Tpm1 axis, thus exerting a therapeutic effect on DVC. CMIT may be a promising approach for the treatment of DVC.

Immunocyte reprogramming empowers live-cell drug delivery: Mechanistic insights, delivery strategies, and clinical perspectives

Zheng Sun, Jun Ge, Hui Fu, Ziqiu Chen, Chengcheng Zhao, Xiuyan Li, Yujiao Sun, Zhonggao Gao, Yunfei Li, Yingpeng Li

Acta Pharmaceutica Sinica B. 2026, 16(1): 169-197.

Conventional drug-delivery systems (DDSs) for oncology often face challenges such as insufficient tumor selectivity, rapid systemic clearance, limited penetration across stromal and immune barriers, and suboptimal biocompatibility. Live immune cell-based drug-delivery systems (LCDDSs) overcome these limitations by exploiting the innate tumor-homing capacity, high biocompatibility, and dynamic tumor microenvironment (TME) interactions intrinsic to leukocytes, facilitating precise targeting with minimal systemic toxicity. Furthermore, immune cells act as “mobile microprocessors”, actively converting precursor payloads into therapeutically functional cargos at the tumor site and dynamically reshaping the TME. Nonetheless, the clinical translation of LCDDSs remains impeded by limited drug-loading capacities, premature payload degradation, potential impairment of immune-cell function, and insufficient persistence in immunosuppressive environments. To overcome these hurdles, immune cell reprogramming via genetic, metabolic, or epigenetic modifications emerges as a promising strategy. Such interventions improve cellular fitness, enhance tumor infiltration, augment payload transport efficiency, confer programmable release profiles, mitigate cellular exhaustion, and increase adaptability to the hostile TME. This review systemically evaluates how immune cell reprogramming advances LCDDSs by examining mechanistic benefits, drug compatibility considerations, payload loading strategies, and design criteria essential for achieving clinical controllability, safety, and scalability. By integrating immune-cell engineering with cutting-edge drug delivery technologies, reprogrammed LCDDSs represent a versatile and powerful platform for next-generation precision oncology therapeutics.

Oxygen-boosted dual-section microneedle patch for enhanced drug penetration and improved photodynamic and anti-inflammatory therapy in psoriasis

Yaqi Yuan, Peng Jiang, Chuan Xiao, Jiapeng Lei, Bo Cheng, Hankun Hu, Wei Li

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.

Transmitophagy in the heart: An overview of molecular mechanisms and implications for pathophysiology

Acta Pharmaceutica Sinica B. 2026, 16(1): 1-12.

Mitochondria are essential for meeting cardiac metabolic demands and their dysfunction is associated with heart failure and is a key mediator of cardiac ischemia-reperfusion injury. Cardiomyocytes engage integrated mechanisms to maintain mitochondrial function; however, chronic stress or disease can overwhelm this capacity. The removal of damaged mitochondria is mediated by a process known as mitophagy, which, together with mitochondrial biogenesis, plays a key role in maintaining mitochondrial quality control. Maintenance of mitochondrial quality control was initially thought to be autonomously regulated within each cellular population with little exchange between cells. However, recently the phenomenon of transmitophagy has been identified in which damaged mitochondria are transferred to neighboring cells for degradation. This review discusses the current understanding of transmitophagy in the context of heart injury, aging and disease, with particular emphasis on exophers, migrasomes, and tunneling nanotubes as pathways mediating cell-cell communication between cardiomyocytes, macrophages and fibroblasts. We further discuss the potential of targeting transmitophagy for cardioprotection and highlight key unanswered questions and challenges. Addressing these gaps may reveal novel strategies to preserve mitochondrial homeostasis and improve the outcomes of patients with cardiovascular disease.