Simple and Smart Metal–Phenolic Micelles for Optimizing Immunotherapy by Disrupting Tumor Stemness

IF 9.1 1区材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Nano Letters Pub Date : 2025-01-10 DOI:10.1021/acs.nanolett.4c05468

Yaping Wang, Xin Wang, Yuping He, Xinni Li, Wenyan She, Lin Hou

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Abstract

cGAS-STING pathway activation has attracted considerable attention in antitumor immunotherapy, but clinical outcomes lag behind expectations due to overlooked negative feedback mechanisms. Here, we determine that STING activation promotes tumor stemness, which weakens the efficacy of STING-based therapies, presenting a double-edged sword. To address this therapeutic paradox, a simple metal-phenolic polymeric micelle (HMQ) was developed, in which Mn²⁺ (a STING agonist) is coordinated with quercetin (a stemness inhibitor) and hyaluronic acid (HA), to unlock the full therapeutic potential of the cGAS-STING pathway. This unique coordination structure integrates active targeting with rapid and pH-responsive drug release. Importantly, the released drugs remained in their original form, avoiding potential changes in bioactivity. HMQ effectively mitigates the stemness-promoting effects of STING activation, thus significantly amplifying the potency of cGAS-STING-based therapies. This intelligent and facile HMQ establishes a new generation of cGAS-STING agonists with promising clinical translatability and provides a flexible platform for the win–win strategy.

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通过破坏肿瘤干性优化免疫治疗的简单和智能金属-酚胶束

cGAS-STING通路激活在抗肿瘤免疫治疗中引起了相当大的关注，但由于忽视了负反馈机制，临床结果落后于预期。在这里，我们确定STING激活促进肿瘤干性，这削弱了基于STING的治疗的疗效，这是一把双刃剑。为了解决这一治疗悖论，研究人员开发了一种简单的金属-酚醛聚合物胶束（HMQ），其中Mn2+（一种STING激动剂）与槲皮素（一种干性抑制剂）和透明质酸（HA）协同作用，以释放cGAS-STING途径的全部治疗潜力。这种独特的协调结构将主动靶向与快速和ph反应性药物释放结合起来。重要的是，释放的药物保持其原始形式，避免了生物活性的潜在变化。HMQ有效地减轻了STING激活的干细胞促进作用，从而显著增强了基于cgas -STING的治疗的效力。这种智能、便捷的HMQ建立了具有临床可翻译性的新一代cGAS-STING激动剂，并为双赢战略提供了灵活的平台。

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来源期刊

Nano Letters 工程技术-材料科学：综合

CiteScore

16.80

自引率

2.80%

发文量

1182

审稿时长

1.4 months

期刊介绍： Nano Letters serves as a dynamic platform for promptly disseminating original results in fundamental, applied, and emerging research across all facets of nanoscience and nanotechnology. A pivotal criterion for inclusion within Nano Letters is the convergence of at least two different areas or disciplines, ensuring a rich interdisciplinary scope. The journal is dedicated to fostering exploration in diverse areas, including: - Experimental and theoretical findings on physical, chemical, and biological phenomena at the nanoscale - Synthesis, characterization, and processing of organic, inorganic, polymer, and hybrid nanomaterials through physical, chemical, and biological methodologies - Modeling and simulation of synthetic, assembly, and interaction processes - Realization of integrated nanostructures and nano-engineered devices exhibiting advanced performance - Applications of nanoscale materials in living and environmental systems Nano Letters is committed to advancing and showcasing groundbreaking research that intersects various domains, fostering innovation and collaboration in the ever-evolving field of nanoscience and nanotechnology.