Research and Progress in the Application of Tumor Microenvironment-Responsive Biodegradable Molecularly Imprinted Nanoparticles
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摘要: 肿瘤治疗是全球医学领域的核心挑战。临床常规化疗、放疗等传统手段因缺乏选择性、易产生耐药性及严重的不良反应，限制了其治疗效果。分子印迹聚合物（molecularly imprinted polymers，MIPs）作为一种具备定制识别空穴的智能材料，能够特异性结合肿瘤靶标，但在体内应用中面临稳定性不佳与代谢清除困难等局限。为开发高效、精准且生物安全性高的新型递送系统，生物可降解分子印迹聚合物（biodegradable molecularly imprinted polymer，BD-MIPs）应运而生。系统综述BD-MIPs的靶向递送机制及其影响因素、构建策略与设计机制，重点阐述其智能控释机制，详细介绍利用肿瘤微环境（tumor microenvironment，TME）特有的触发药物释放的内源性策略，以及基于光、热等外部触发条件的一体化诊疗方案。最后，讨论BD-MIPs在释药动力学和生物相容性方面存在的不足，并分析其未来发展面临的挑战与前景。不仅凸显了其作为肿瘤精准治疗创新平台的巨大潜力，更为突破现有研究局限、推动其迈向广泛临床转化提供了策略借鉴。Abstract: Tumor treatment remains a core challenge in global medical research. Conventional therapeutic modalities such as chemotherapy and radiotherapy suffer from lack of selectivity, propensity for drug resistance, and severe adverse reactions, which limit their therapeutic efficacy. Molecularly imprinted polymers （MIPs）, as intelligent materials with customizable recognition cavities, can specifically bind tumor targets; however, their in vivo applications face limitations including poor stability and difficulties in metabolic clearance. To develop efficient, precise, and highly biocompatible novel delivery systems, biodegradable molecularly imprinted polymers （BD-MIPs） have emerged. This review systematically examines the targeted delivery mechanisms of BD-MIPs and their influencing factors, construction strategies, and design principles, with emphasis on their intelligent controlled-release mechanisms. It details endogenous strategies for drug release triggered by the unique characteristics of the tumor microenvironment （TME）, as well as integrated theranostic approaches based on external triggers such as light and heat. Finally, it discusses the limitations of BD-MIPs in drug release kinetics and biocompatibility, analyzes challenges and prospects for future development, and highlights the tremendous potential of BD-MIPs as an innovative platform for precision cancer therapy. Furthermore, it provides strategic guidance for overcoming current research limitations and advancing their translation toward broad clinical application.
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Key words:
- Molecularly imprinted polymers /
- Biodegradable /
- Nanoparticles /
- Cancer therapy /
- Drug delivery
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图 1 分子印迹聚合物与目标分子相互作用的机理示意图
A：模板分子通过非共价组装、共价修饰或配体交换等方式与功能单体结合；B：加入交联剂进行聚合反应；C：洗脱去除模板后，聚合物中留下具有特异性识别能力的定制印迹空穴，从而实现对目标分子的可逆缔合与解离。
Figure 1. Schematic diagram of the interaction mechanism between molecularly imprinted polymers and target molecules
图 2 BD-MIPs的构建、智能控释机制和应用前景与挑战示意图
A：利用聚合物单体、交联剂与靶标分子，通过精准的聚合反应设计与制备BD-MIPs纳米材料的过程；B：BD-MIPs如何利用TME的特有属性（微酸性、高浓度谷胱甘肽、缺氧和特定酶的高表达）作为内源性触发器，结合外部刺激（光热治疗 PTT），实现靶向识别、精准释药与诊疗一体化；C：BD-MIPs在实现肿瘤靶向递送、降低正常组织不良反应等的潜力与亟待克服的挑战。
Figure 2. Schematic diagram of the construction of BD-MIPs，their intelligent controlled-release mechanism，and the prospects and challenges of their applications
图 3 BD-MIPs的靶向递送机制及深层穿透挑战示意图
A：被动靶向机制与理化性质不足示意图；B：BD-MIPs主动靶向示意图；C：BD-MIPs实现深层靶向亟待解决瓶颈示意图。
Figure 3. Schematic diagram of the targeted delivery mechanisms of BD-MIPs and the challenges of deep tumor penetration
图 4 生物可降解分子印迹聚合物（BD-MIPs）基于肿瘤微环境（TME）与多重刺激响应的智能控释机制及诊疗一体化平台示意图
A：BD-MIPs在血液（pH 7.4，低GSH）中保持稳定，在肿瘤微环境（低pH、高GSH、特定酶）中响应性释放；B：pH响应通过叔胺基团实现血液中锁定，肿瘤中释放；GSH响应通过二硫键实现血液中交联稳定，肿瘤中通过硫醇-二硫键交换释放自由硫醇； C：在局部酸性及酶靶点处被酶激活，利用酶异质性增强治疗效果；D：针对肿瘤异质性，通过提高二硫键比例增强GSH响应，并增加酶敏感肽段；E：结合多种响应策略及外部刺激（温度、光、磁场），实现肿瘤靶向治疗。
Figure 4. Schematic illustration of the intelligent controlled-release mechanisms and integrated theranostic platform of biodegradable molecularly imprinted polymers （BD-MIPs） based on tumor microenvironment （TME） and multi-stimuli responsiveness
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