Yadav Pankaj, Yadav Amit K, Bhatia Dhiraj
Department of Biotechnology, School of Energy Technology, Pandit Deendayal Energy University, Knowledge Corridor, Gandhinagar, Gujarat 382007, India.
Department of Biological Sciences and Engineering, Indian Institute of Technology Gandhinagar, Near Palaj, Gandhinagar, Gujarat 382355, India.
ACS Biomater Sci Eng. 2025 Nov 10;11(11):6401-6425. doi: 10.1021/acsbiomaterials.5c01120. Epub 2025 Oct 7.
The tumor microenvironment (TME) is a critical orchestrator of cancer progression, shaped not only by genetic mutations but also by dynamic factors such as acidic pH, dysregulated extracellular matrix (ECM), immunosuppressive cells, and cytokine networks. These elements collectively foster therapeutic resistance and metastasis, challenging conventional treatments. Nanotechnology has emerged as a transformative approach to dismantling TME barriers, enabling precise targeting and enhanced drug delivery. In addition, a key focus is overcoming ECM density and immunosuppression. For instance, ECM-degrading nanoparticles (NPs) loaded with hyaluronidase or collagenase improve drug penetration, while immune-modulating NPs reprogram macrophages from protumor (M2) to antitumor (M1) phenotypes. Complementing these strategies, advances in immune cell engineering, such as chimeric antigen receptor (CAR) T cells or natural killer (NK) cells, are synergized with NPs-delivered checkpoint inhibitors to amplify antitumor immunity. Additionally, pH-sensitive and enzyme-responsive NPs exploit TME-specific conditions for controlled drug release, minimizing systemic toxicity. Despite promising preclinical results, clinical translation faces hurdles. Challenges include optimizing NPs' biocompatibility, scalability, and long-term safety as well as addressing interpatient TME heterogeneity. Thus, this review explores innovative NPs designs engineered to navigate the TME complexity, including surface modifications with antibodies, folic acid, transferrin, peptides, and amino acids. These functionalized NPs improve tumor-specific targeting while evading immune clearance, thereby enhancing chemotherapeutic efficacy and reducing off-target effects. Moreover, this review evaluates current progress in NPs-based clinical trials targeting the TME and discusses emerging theranostic platforms that combine real-time imaging with therapy. By integration of multidisciplinary insights from materials science, immunology, and systems biology, nanotechnology holds immense potential to unlock personalized cancer therapies. Future research must prioritize scalable manufacturing and robust biomarker-driven approaches to realize this paradigm shift in oncology fully.
肿瘤微环境（TME）是癌症进展的关键协调者，其形成不仅受基因突变影响，还受酸性pH值、失调的细胞外基质（ECM）、免疫抑制细胞和细胞因子网络等动态因素影响。这些因素共同促进治疗抗性和转移，给传统治疗带来挑战。纳米技术已成为一种变革性方法，可消除TME障碍，实现精准靶向和增强药物递送。此外，一个关键重点是克服ECM密度和免疫抑制。例如，负载透明质酸酶或胶原酶的ECM降解纳米颗粒（NPs）可改善药物渗透，而免疫调节性NPs可将巨噬细胞从促肿瘤（M2）表型重编程为抗肿瘤（M1）表型。作为这些策略的补充，免疫细胞工程的进展，如嵌合抗原受体（CAR）T细胞或自然杀伤（NK）细胞，与NPs递送的检查点抑制剂协同作用，以增强抗肿瘤免疫力。此外，pH敏感和酶响应性NPs利用TME特异性条件进行可控药物释放，将全身毒性降至最低。尽管临床前结果很有前景，但临床转化面临障碍。挑战包括优化NPs的生物相容性、可扩展性和长期安全性，以及解决患者间TME异质性问题。因此，本综述探讨了为应对TME复杂性而设计的创新NPs设计，包括用抗体、叶酸、转铁蛋白、肽和氨基酸进行表面修饰。这些功能化NPs改善了肿瘤特异性靶向，同时避免了免疫清除，从而提高了化疗疗效并减少了脱靶效应。此外，本综述评估了基于NPs的针对TME的临床试验的当前进展，并讨论了将实时成像与治疗相结合的新兴治疗诊断平台。通过整合材料科学、免疫学和系统生物学的多学科见解，纳米技术具有释放个性化癌症治疗方法的巨大潜力。未来的研究必须优先考虑可扩展制造和强大的生物标志物驱动方法，以充分实现肿瘤学的这一范式转变。
