8 selected pharmaceutical heavyweight achievements in this issue: DNA guided CRISPR reverse regulation of RNA, precise and reversible; Sun Yat sen University reveals that the HNRNPD-GRAMD4 axis mediates radiotherapy resistance in nasopharyngeal carcinoma; Nanjing University and others discovered that the CD40-TRAF2/3/5 pathway drives post myocardial infarction repair; Chongqing Medical University constructs a time-series responsive nano platform for the treatment of intestinal ischemia-reperfusion; Wang Dapeng’s team developed hydrogel microneedle composite dressing to promote the healing of diabetes wounds; Targeted delivery of GGT1 degradation agent by University of Science and Technology of China for repairing spinal cord injury; Shaanxi Normal University elucidates the regulatory mechanism of SPARC-VEGFR2-CD59 axis in rare brain diseases; Shandong University found that fibroblast CCN1 aggravated heart disease in diabetes. Welcome to learn!

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1、 Nat Biotechnol: CRISPR’s “Reverse Operation” – DNA Guided Precise Regulation of Cellular RNA

Recently, a research team from the University of Florida published a groundbreaking study in the top tier journal Nature Biotechnology, overturning the traditional framework of the CRISPR system relying on RNA guides and developing a new CRISPR targeted regulation technology mediated by DNA guides. This technology achieves precise and reversible regulation of intracellular RNA, opening up a new direction for gene function research, molecular diagnosis, and clinical gene therapy.

The traditional CRISPR Cas system, which uses RNA as a guiding molecule, has made many breakthroughs in the field of DNA editing. However, RNA guides have inherent defects such as poor in vitro storage stability, high synthesis costs, and irreversible DNA editing results. The safety risks of long-term clinical applications have not been fully resolved.

The novel guide DNA designed in this study reverse reconstructed the target binding conformation of natural crRNA through sequence backbone modification, which can guide Cas12 nuclease to specifically recognize RNA targets. Clinical validation shows that the accuracy of clinical sample detection of hepatitis C virus RNA by PSI DNA is 100%; In various human cell lines, the multiple knockdown efficiency of endogenous RNA transcripts can reach 70% to 95%, and the off target effect is much lower than that of traditional RNA guides. In addition, PSI DNA is fully compatible with traditional crRNA and can mediate synchronous DNA editing and RNA knockdown of the same AsCas12a protein, without interfering with each other.

This platform can be modularly expanded and modified. The DNA guide has the advantages of easy synthesis, low cost, and high stability, and RNA regulation is a reversible operation, greatly improving the safety of long-term applications. It has broad prospects for transformation in the field of biomedicine.

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2、 Zhongshan team reveals new mechanism of nasopharyngeal carcinoma resistance to radiotherapy and proposes a solution

Nasopharyngeal carcinoma is a highly prevalent malignant tumor in the head and neck region of southern China. Radical radiotherapy is the first-line treatment for early nasopharyngeal carcinoma, but nearly 30% of patients may develop primary or acquired radiation resistance, leading to recurrence and metastasis, which is the main obstacle to improving clinical prognosis. Stress granules (SGs), as membraneless RNA protein aggregates formed under cellular stress, have been shown to be associated with resistance to various tumor treatments, but their mechanism of action in nasopharyngeal carcinoma radiotherapy resistance has long been unclear. Recently, Xia Jianchuan’s team from Sun Yat sen University published their latest research in the international authoritative journal Advanced Science, analyzing the core regulatory pathways of this process and providing a new target for radiosensitization of nasopharyngeal carcinoma.

This study first confirmed that SG is a key functional structure mediating radiotherapy resistance in nasopharyngeal carcinoma. Inhibiting SG formation or knocking out the SG core assembly gene G3BP1 can significantly enhance the radiotherapy sensitivity of nasopharyngeal carcinoma cells. Further research identified heterogeneous nuclear ribonucleoprotein D (HNRNPD) as a key SG related regulatory RNA binding protein through screening. This protein is significantly upregulated in nasopharyngeal carcinoma radiation resistant tissues, and its expression level is significantly positively correlated with poor patient prognosis.

Mechanism studies have shown that HNRNPD promotes SG assembly, retains the mRNA of the pro apoptotic gene GRAMD4 in the SG functional region, inhibits the protein translation of GRAMD4, and blocks the mitochondrial apoptosis pathway, ultimately promoting tumor cell survival after radiotherapy; Functional validation confirms that restoring GRAMD4 expression can effectively reverse radiotherapy resistance in nasopharyngeal carcinoma. This study has improved the molecular regulatory network of radiotherapy resistance in nasopharyngeal carcinoma, suggesting that targeting the SGs or HNRNPD-GRAMD4 signaling axis may break through the resistance bottleneck and provide a clear direction for the development of radiosensitizing drugs in the future.

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3、 Mechanism breakthrough in myocardial infarction repair, precise targeting of CD40 heterogeneous signaling opens up new therapeutic directions

Currently, acute myocardial infarction remains the leading cardiovascular disease causing death and disability worldwide. After the popularization of reperfusion therapy, poor ventricular remodeling induced by repair dysfunction in the infarcted area still leads to long-term heart failure in nearly 30% of patients. Analyzing the immune regulatory mechanism of repair after heart injury is the core requirement for developing a new generation of targeted treatment plans. On May 7th, Zhang Longjiang’s team from Nanjing University and Bu Jun’s team from Shanghai Jiao Tong University collaborated to publish a groundbreaking study in the top cardiovascular journal Circulation, which for the first time clarified the heterogeneity of CD40 signaling function in macrophages, providing a precise targeted new strategy for the treatment of myocardial infarction.

This study focuses on macrophage mediated phagocytosis, a core biological process that regulates inflammation resolution and benign tissue remodeling in the infarcted area. It confirms that CD40 is a key regulatory molecule driving this process. The study found that CD40 expression on the surface of infiltrating myeloid macrophages after myocardial infarction was significantly upregulated, and downstream different TRAF family molecules mediated complete differentiation. Traditionally, the TRAF6 pathway was thought to mainly mediate pro-inflammatory responses, but this study is the first to clarify that CD40 can selectively activate STAT6 signaling through downstream TRAF2/3/5, significantly enhance macrophage phagocytosis ability, accelerate the clearance of apoptotic inflammatory cells, and improve cardiac repair.

In vivo functional verification has confirmed that macrophage specific CD40 deficiency significantly impairs phagocytic function and worsens cardiac function; Overexpression of CD40 variants that only retain the TRAF2/3/5 binding site can restore cellular phagocytosis and improve long-term cardiac function. This study has resolved the long-standing controversy in the field regarding CD40 function, avoided off target risks of pan CD40 targeting, and provided a clear molecular basis for the development of selective myocardial infarction treatment drugs, with outstanding clinical translational value.

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4、 Chongqing Medical University team solves the problem of intestinal ischemia-reperfusion treatment

Intestinal ischemia-reperfusion (I/R) injury is a common and serious complication after shock resuscitation, intestinal obstruction, major abdominal surgery, and intestinal transplantation. It has a biphasic pathological feature of “acute phase oxidative inflammation outbreak and subacute phase repair dysfunction”. Existing intervention methods are limited in clinical efficacy due to their inability to adapt to the pathological needs of the disease course, making it a prominent unmet clinical need in the fields of critical illness and digestive surgery.

Recently, the team led by Li Tong from Chongqing Medical University published their latest research in the top international interdisciplinary journal Advanced Science, successfully developing multifunctional time-series responsive nanocomposites MPB@TA-Cu-Ma We have achieved adaptive synchronous biphasic therapy for intestinal I/R injury. The nano platform is based on mesoporous Prussian blue and modified by tannic acid (TA) etching, which significantly improves the specific surface area and drug loading capacity. At the same time, a large number of phenolic hydroxyl groups on the surface can directly remove reactive oxygen species (ROS); Further ion exchange was used to replace some Fe ³ ⁺ in the matrix with Cu ² ⁺, which not only enhanced the ability to clear ROS through multiple pathways, but also endowed the nano platform with endogenous pro angiogenic activity; The final package of anti-inflammatory protein MaR1 achieved precise temporal regulation of macrophage function.

In vitro and in vivo experiments have confirmed that the nano platform can efficiently clear excess ROS during the acute phase of I/R injury, inhibit NLRP3 inflammasome mediated cell pyroptosis, and block inflammatory storms; During the 96 hour repair period after injury, sustainable promotion of intestinal mucosal epithelial proliferation and neovascularization significantly restores the integrity of the intestinal mucosal barrier. This study provides a new design paradigm for precise treatment of bipolar diseases, with clear clinical translational potential.

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5、 Wang Dapeng and other teams designed composite dressings for the treatment of chronic wounds of diabetes

The global prevalence of diabetes continues to rise. diabetes chronic refractory wounds have become a high incidence of clinical chronic complications. Such wounds have typical pathological microenvironment spatial heterogeneity – the surface layer is often accompanied by abnormal exudation, bacterial colonization, and the deep layer is often accompanied by vascular injury, excessive inflammatory infiltration, and abnormal fibrosis remodeling. The existing clinical programs such as debridement, negative pressure drainage, and conventional external dressings have limited efficacy and are prone to induce side effects such as infection recurrence, allergy, and the development of new precision treatment strategies is the core demand in the field of regenerative medicine.

Recently, Wang Dapeng’s team from Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, published the latest research results in the international top material journal Advanced Materials, successfully constructed a hydrogel based composite wound dressing (H @ MN) integrated with a soluble microneedle array, realized the time-space cascade reaction collaborative treatment for chronic diabetes wounds, and broke through the existing technical bottleneck.

The traditional hydrogel dressing only acts on the surface of the wound and cannot penetrate the necrotic scab skin barrier to interfere with deep pathological abnormalities; Single polymer based soluble microneedles commonly suffer from the limitation of limited drug loading, making it difficult to meet the long-term treatment needs of chronic wounds. This research innovatively integrates the advantages of hydrogel in moisturizing, promoting healing, exudation absorption and transdermal delivery of microneedles, and combines photothermal therapy to build a cascade reaction system: achieve full coverage regulation of the surface deep pathological microenvironment in space, complete the sequential treatment of rapid response and sustained release in time, successfully overcome the core challenge of spatial heterogeneity of pathological factors, and achieve efficient healing of chronic wounds of diabetes. This integrated design provides a universal research and development approach for chronic wounds, transdermal drug delivery, and other fields, with good clinical translation prospects.

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6、 Chinese University of Science and Technology and other teams accurately deliver GGT1 degradation agent to assist in the repair and regeneration of spinal cord neurons

Spinal cord injury, as a highly prevalent central nervous system trauma in clinical practice, still lacks effective treatment methods due to irreversible neuronal death after injury and the difficulty of drugs breaking through physiological barriers to achieve targeted enrichment at the injury site. Developing new precise intervention strategies is the core research direction in this field. Recently, the team led by You Tao from the University of Science and Technology of China, in collaboration with relevant research institutions, published the latest results in the international authoritative journal Advanced Science. By accurately delivering gamma glutamyltransferase 1 (GGT1) degradation agent, they achieved the repair and regeneration of spinal cord injury neurons, providing a new target and translational strategy for the clinical treatment of this disease.

This study first verified through clinical samples and animal models that GGT1 is a key driving factor for neuronal ferroptosis after spinal cord injury, and its expression is significantly upregulated in neurons after injury, making it a highly promising new intervention target. The research team screened and obtained anthocyanins (EA) from a natural product library, confirming that EA can specifically bind to GGT1 and recruit E3 ubiquitin ligase MGRN1 to mediate ubiquitination modification of GGT1 and degrade it through the proteasome pathway, effectively inhibiting neuronal ferroptosis.

To address the bottleneck of poor stability and low in vivo targeting efficiency of small molecule EA, the team further constructed a biomimetic nano delivery platform for neural stem cell membranes NSCm@EA By utilizing the homologous targeting properties of neural stem cell membranes, precise delivery of EA to injured spinal cord neurons can be achieved, effectively reshaping functional neuronal subpopulations in the injured area. This study has opened up a complete path of “new target discovery specific degradation agent screening precise delivery system construction”, solved the core problem of targeted drug intervention for spinal cord injury, and provided a new idea for the translational research and development of spinal cord injury treatment.

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7、 The Shaanxi Normal University team reveals the cause of cell “fire extinguisher” failure in rare brain diseases

Neuromyelitis optica spectrum disorder (NMOSD) is a rare inflammatory demyelinating brain disease of the central nervous system that is highly prevalent in women. The core pathogenesis of NMOSD is astrocyte damage mediated by complement overactivation. Currently, the mechanism by which cell interactions regulate complement homeostasis in the brain microenvironment is still unclear, and there is still an unmet need for targeted therapy in clinical practice. Recently, Yan Yaping’s team from Shaanxi Normal University published the latest research in the international journal Nature Communications, clarifying the molecular mechanism of complement activation regulated by brain endothelial astrocyte communication, providing a potential new direction for precision treatment of NMOSD.

This study confirms that the endogenous complement inhibitory protein CD59 on the surface of astrocytes is a core negative regulatory factor for complement activation, which can protect cells by blocking the assembly of pathogenic membrane attack complex MAC. Abnormal function is equivalent to the failure of the “fire extinguisher” for complement regulation in cells. The team validated the NMOSD disease model using female mice and found that SPARC protein secreted by brain endothelial cells can directly inhibit the VEGFA/VEGFR2 signaling pathway, downregulate CD59 expression in astrocytes, and induce complement overactivation and astrocyte damage; The specific deficiency of SPARC in endothelial cells or pharmacological activation of VEGFR2 can upregulate CD59 expression and significantly alleviate central inflammatory demyelinating lesions.

This research system clarifies the regulatory rules of SPARC/VEGFR2 axis on CD59, elucidates the core role of endothelial astrocyte communication in the pathogenesis of NMOSD, and lays the molecular foundation for the development of novel therapeutic strategies targeting astrocytes.

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8、 Shandong University found that fibroblasts release CCN1 to aggravate heart disease in diabetes

Recently, the team led by Xu Bin from Southeast University published the latest research in the international authoritative journal Cell Reports, revealing the key driving factors of NEPC occurrence and verifying the clinical translational potential of old drugs for new use.

This study conducted single-cell RNA sequencing on prostate transgenic adenocarcinoma model mice at different stages of pathological progression, and identified early neuroendocrine initiating cell subsets through cell trajectory analysis. It was found that the core molecular feature of this subset is the significant upregulation of the homologous box gene HOXD11, which is conserved in human NEPC clinical samples. Functional validation shows that knocking down HOXD11 can effectively block the neuroendocrine differentiation program of tumors, restore the activity of the androgen receptor (AR) signaling pathway in drug-resistant tumors, and reverse the endocrine therapy resistance phenotype.

Mechanism studies have shown that HOXD11 can promote neuroendocrine transformation by transcriptional activation of downstream FOXA2 and N-methyl-D-aspartate receptor (NMDAR) subunit pathways, which are significantly associated with poor prognosis in NEPC patients. The research team used the clinically approved NMDAR antagonist memantine for intervention and confirmed that it can significantly inhibit tumor progression in preclinical NEPC models. One refractory NEPC patient who failed multi line chemotherapy achieved clear imaging relief after treatment with memantine.

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This study is the first to clarify that HOXD11 is a key driver of neuroendocrine transformation in NEPC, providing a new modifiable target for refractory NEPC and laying a solid theoretical and practical foundation for subsequent clinical exploration of memantine.

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