Core Viewpoint - The article discusses a groundbreaking method for drug delivery to the central nervous system (CNS) by utilizing calvarial immune cells to bypass the blood-brain barrier (BBB), which has significant implications for treating CNS diseases [4][5][15]. Group 1: Blood-Brain Barrier and Drug Delivery Challenges - The blood-brain barrier (BBB) is crucial for preventing harmful substances from entering the brain but also limits the delivery of most small and large molecule drugs, hindering treatment for CNS diseases [2][7]. - The high failure rate of clinical trials for CNS drugs is primarily due to the inability of most drugs to cross the BBB, leading to insufficient drug accumulation in the brain and poor therapeutic outcomes [7][8]. Group 2: Innovative Drug Delivery Method - A research team from Tsinghua University and Beijing Tiantan Hospital published a study in Cell, demonstrating that drug-loaded nanoparticles can "hijack" calvarial immune cells to deliver drugs to the CNS by utilizing the skull-meninges channel (SMC) to bypass the BBB [4][10]. - The study confirmed that this method significantly improved short-term and long-term outcomes in preclinical stroke models [4][5]. Group 3: Clinical Trial and Safety - A prospective clinical trial (SOLUTION, NCT05849805) was conducted to assess the safety and feasibility of this method in patients with malignant middle cerebral artery infarction (mMCAI), showing that the intracranial injection procedure is simple and does not cause severe complications [13][15]. - The real-world data from this trial highlights the potential for clinical translation of this innovative drug delivery strategy [13][15]. Group 4: Mechanism and Efficacy - The study utilized albumin nanoparticles that exhibit a tendency to be internalized by immune cells, which then migrate to the CNS injury sites, significantly accumulating in neurons at the damaged areas [12]. - The treatment with drug-loaded nanoparticles demonstrated superior efficacy in reducing ischemic infarction and brain edema compared to conventional methods, achieving these effects with only 1/15 of the usual dosage [12].

Core Viewpoint - The article discusses a breakthrough in T cell therapy through chemical reprogramming, which allows mature T cells to be converted into pluripotent stem cells, potentially addressing current limitations in immunotherapy [3][6]. Group 1: Research Breakthrough - The research team from Peking University successfully reprogrammed human T cells into pluripotent stem cells using a chemical approach, overcoming the limitations of traditional methods that rely on transcription factors [7][8]. - The method involves a two-phase process: the initial phase uses a small molecule cocktail to induce T cell aggregation and loss of T cell characteristics, followed by activation of pluripotency genes to produce T cell-derived pluripotent stem cells (hT-CiPS) [8]. Group 2: Characteristics of hT-CiPS Cells - hT-CiPS cells retain the T cell receptor (TCR) gene rearrangement, which is crucial for recognizing specific antigens, thus preserving the diversity of the original T cell population [11][19]. - The generated hT-CiPS cells are highly similar in morphology and gene expression to human embryonic stem cells, indicating their potential for further applications in immunotherapy [10][11]. Group 3: Differentiation and Production - hT-CiPS cells can efficiently differentiate back into T cells, with a high success rate in producing CD3+ T cells that express TCRs, ensuring the specificity is maintained [13][15]. - The research indicates that 99.8% of the TCR sequences in the newly generated T cells match those of the parent hT-CiPS cells, confirming the fidelity of the reprogramming process [13]. Group 4: Future Applications - The chemical reprogramming platform could enable the industrial-scale production of "off-the-shelf" T cell products, significantly reducing costs and wait times for patients [15]. - The method's high safety profile, due to the use of small molecules without gene integration risks, and its ability to capture TCR diversity, positions it as a promising advancement in regenerative medicine and immunotherapy [19].

然而，现有蛋白质降解技术在 体内应用 时，往往难以同时兼顾 时间选择性 和 空间选择性 ，导致降解效率受限，并面临 脱靶风险 。 因此，如何在复杂生命体系中实现蛋白质降解的 时空精准调控 ，是化学生物学和生命科学研究的核心挑战之一。 撰文丨王聪 编辑丨王多鱼 排版丨水成文 近年来，包括分子胶、蛋白靶向降解嵌合体 （PROTAC） 等在内的 靶向蛋白降解 （ Targeted protein degradation， TPD） 技术已崭露头角，成为颇具前景 的治疗手段，其依赖于泛素蛋白酶体系统 （UPS） 来降解蛋白质， 彻底改变了基础生物学和药物研发中调控蛋白质功能的策略。 2026 年 1 月 16 日，中国科学院化学研究所 汪铭 团队在国际顶尖学术期刊 Cell 上发表了题为： Multimodal supramolecular targeting chimeras enable spatiotemporally resolved protein degradation in vivo 的研究论文。 该研究开发了 超分子靶向嵌合体 （SupTAC） 技术， 首次在活体动物模型中实现 可编程 、 时空可控的 ...

撰文丨王聪 编辑丨王多鱼 排版丨水成文 衰老 是一个复杂的过程，会影响各种组织和器官，同时伴有衰老细胞的积聚。衰老细胞表现出增殖不可逆停滞以及对程序性细胞死亡的抵抗。重要的是，衰老细 胞能够分泌多种促炎细胞因子、趋化因子和组织重塑蛋白，这些统称为 衰老相关分泌表型 （SASP） 。 SASP 已被证实与衰老相关的退行性疾病发病机制有关，已有大量证据表明，通过药物或基因手段清除衰老细胞 （也被称为 Senolytics ） 是一种有效的抗衰老 方法。近年来，新研发的 Senolytics 药物已被证实能够特异性地清除衰老细胞，且副作用较小。 但目前尚不清楚 低气压 （Hypobaric Pressure，HP） 是否能 够诱导衰老细胞死亡。 衰老细胞 的积聚会导致 衰老 ，清除这些衰老细胞是一种有效的抗衰老策略。目前的抗衰老策略侧重于药物介导的衰老细胞清除，尚不清楚 低气压 条件是否能够 诱导衰老细胞死亡。 低气压 （HP） 是指低于标准大气压的相对压力状态，它既是高海拔地区的自然条件，也存在于人体内部。人体内低气压的分布是生物进化与适应性的重要体 现。低气压对于维持心脏、肺、腹腔、胃肠道及关节的基本生命活动至 ...

Core Insights - The study indicates that Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a diurnal disease influenced by multi-system insulin resistance and reduced insulin availability at night [3][9] - The severity of MASLD and related metabolic disorders exhibits significant diurnal fluctuations, with nighttime being the period of most severe metabolic issues, providing new insights for optimal timing of diet, exercise, and medication for patients [3][12] Summary by Sections - **Introduction to MASLD**: MASLD affects approximately 40% of the global population and is closely linked to obesity and insulin resistance (IR). It is characterized by excessive triglyceride (TAG) accumulation in liver cells, which can progress to Metabolic Dysfunction-Associated Steatotic Hepatitis (MASH), cirrhosis, and hepatocellular carcinoma [5] - **Mechanisms of MASLD**: The pathogenesis of MASLD depends on the imbalance between lipid influx and synthesis versus clearance in the liver. TAG in the liver originates from fatty acid esterification, which can come from fat tissue breakdown, dietary intake, or de novo lipogenesis (DNL) [5] - **Circadian Influence on Metabolism**: Preclinical models show that liver metabolic homeostasis is strongly influenced by biological clocks, which synchronize physiological functions and behaviors over a 24-hour cycle. Disruption of these rhythms can lead to adverse metabolic outcomes, including liver steatosis [6] - **Research Findings**: The study analyzed diurnal metabolic phenotypes in MASLD patients and overweight controls using advanced stable isotope techniques. Key findings include significant nighttime metabolic dysfunction in MASLD, with activated pathogenic pathways such as hepatic and peripheral insulin resistance, DNL, and systemic NEFA exposure [7][9] - **Persistent Nighttime Dysfunction**: Even after weight loss and reduction of liver fat, nighttime metabolic dysfunction persists, suggesting it may be a primary driver of steatosis [8] - **New Treatment Strategies**: The research suggests a new therapeutic approach—time therapy. This includes scheduling most caloric intake during the day when insulin sensitivity is higher, exercising during less favorable metabolic periods, and adjusting medication timing based on the disease's circadian characteristics to maximize efficacy [12]

Core Viewpoint - Cancer immunotherapy, particularly immune checkpoint blockade (ICB) therapy, has transformed cancer treatment, but a significant proportion of patients do not respond, highlighting the need to understand factors affecting ICB efficacy [2][3]. Group 1: Research Findings - The study published by Dan R. Littman's team indicates that gut microbiota-induced T cell plasticity enables immune-mediated tumor control, suggesting that targeting gut microbiota could enhance ICB therapy effectiveness [3][7]. - The research utilized segmented filamentous bacteria (SFB) to investigate how its colonization in the small intestine influences the efficacy of ICB therapy against tumors expressing SFB antigens [5][6]. - It was found that effective anti-PD-1 treatment in mice only occurred when SFB was present in the gut, leading to the identification of SFB-specific T H 1-like cells that produce high levels of pro-inflammatory cytokines, enhancing tumor control [6][7]. Group 2: Mechanistic Insights - The study elucidates a cellular pathway where a specific gut symbiotic bacterium enhances the efficacy of PD-1 blockade therapy by imparting T cell plasticity [7]. - Conditional removal of IL-17A+ CD4+ T cells, which are precursors to tumor-associated T H 1-like cells, completely abolished the tumor control mediated by anti-PD-1 therapy, indicating their critical role in the tumor microenvironment [6].

撰文丨王聪 编辑丨王多鱼 排版丨水成文 卵巢癌 （ Ovarian Cancer， OC） 是致死率最高的妇科恶性肿瘤，2022 年全球新增病例 324938 例，死亡病例 206834 例。以铂类药物为基础的化疗联合紫 杉醇 （可选择加用或不加用贝伐珠单抗） ；近年来，还会在此基础上联合维持治疗的 PARP 抑制剂和/或贝伐珠单抗，是晚期卵巢癌的主要治疗选择。 尽管当前的卵巢癌一线治疗的应答率为 75% - 80%，但大多数患者在 18 个月内仍会出现癌症复发。对于 铂耐药卵巢癌 ，标准的非铂类化疗疗效有限，仅有 ≤15% 的患者出现客观缓解，中位无进展生存期 （PFS） 在 3 - 4 个月之间 。因此， 临床上迫切需要新型安全有效的抗血管生成药物用于铂耐药卵巢癌的治 疗。 2026 年 1 月 9 日，中国医学科学院肿瘤医院 吴令英 教授 、 山东第一医科大学附属肿瘤医院（山东省肿瘤医院） 李清水 教授等，在 Nature 子刊 Nature Cancer 上发表了题为： Suvemcitug plus chemotherapy in women with platinum-resistant recu ...

Core Viewpoint - Obesity is a significant global public health crisis linked to various chronic diseases, characterized by persistent low-grade inflammation that exacerbates disease progression [6][7]. Group 1: Research Findings - A study published in Science reveals that obesity reshapes macrophage nucleotide metabolism, leading to hyperactivation of the NLRP3 inflammasome and uncontrolled inflammation, accelerating disease progression [3][4]. - The study identifies SAMHD1 as an intrinsic inhibitor in macrophages that can suppress NLRP3 inflammasome activation across species from fish to humans [3]. Group 2: Mechanisms of Inflammation - The NLRP3 inflammasome acts as an "alarm" in the immune system, activated by tissue damage or stress, producing pro-inflammatory cytokines like IL-1β, which, in obesity, disrupt insulin signaling and accelerate metabolic diseases [9]. - Obese individuals exhibit an increased amount of oxidized mitochondrial DNA (ox-mtDNA) in their immune cells, which activates the NLRP3 inflammasome [11][12]. Group 3: Role of SAMHD1 - SAMHD1 is crucial for maintaining nucleotide balance in cells, and obesity leads to its phosphorylation and functional impairment, resulting in excessive NLRP3 inflammasome activation [14]. - The absence of functional SAMHD1 in animal models leads to NLRP3 hyperactivation, indicating its role as a regulatory mechanism against inflammation [14]. Group 4: Metabolic Reprogramming - Obesity alters the metabolic pathways in immune cells, allowing excess dNTPs to enter mitochondria via nucleotide transport proteins, bypassing normal synthesis pathways and leading to uncontrolled mtDNA synthesis [16]. - Blocking dNTP transport into mitochondria can reverse obesity-related inflammation, suggesting a potential therapeutic direction [16]. Group 5: Clinical Implications - Mice lacking SAMHD1 exhibit typical metabolic abnormalities after a high-fat diet, and blocking dNTP transport alleviates these symptoms [18]. - The study's findings indicate that targeting mitochondrial dNTP transport could lead to new therapies for chronic inflammation and metabolic diseases associated with obesity, offering a more precise approach than traditional immune response suppression methods [18].

Core Insights - The article discusses the challenges in clinical trials targeting cancer-associated fibroblasts (CAFs), which are crucial tumor-promoting factors, due to their inherent functional plasticity and the opaque regulatory circuits behind their heterogeneous phenotypes [2] Group 1: Research Findings - A study published in Cancer Cell identified ADAM12 as a fibroblast checkpoint that impedes anti-tumor immunity, with its deletion delaying tumor progression and making tumors more sensitive to immunotherapy [3] - The research team developed a systematic screening method based on complementary CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa) to screen patient-derived fibroblasts [5] - The study found that the I-type interferon (IFN-I) response program is a primary antagonistic axis against TGF-β-driven tumor-promoting myofibroblast activation, with ADAM12 mediating this relationship [5] Group 2: Implications for Treatment - Deletion of ADAM12 triggers the IFN-I response program, reconfiguring the myofibroblast population into progenitor-like states, revitalizing T-cell-based immune responses, and inducing tumor rejection in various mouse models [5] - The research positions ADAM12 as a potential target for therapeutic interventions, paving the way for future treatment strategies [5][7] - The study emphasizes the conversion of TGF-β dependent myCAF programs into IFN-I response states to exert anti-tumor activity, enhancing T-cell infiltration and sensitivity to immunotherapy [7]

Core Viewpoint - The article discusses the first direct observation of the Migdal effect, a significant breakthrough in physics that could aid in the exploration of light dark matter and address a long-standing theoretical gap in the field [3][4]. Group 1: Research Findings - The research team successfully observed the Migdal effect by bombarding gas molecules in a detector with neutrons, distinguishing the "co-vertex" images of simultaneous nuclear and electronic events from complex background noise [6]. - This discovery marks the end of an 80-year wait in the physics community for direct evidence of the Migdal effect, solidifying its theoretical foundation [4][10]. Group 2: Implications - The direct observation of the Migdal effect fills a long-existing experimental validation gap and brings humanity closer to unraveling the mysteries of the universe, particularly regarding dark matter [10].