Tumor responsive nanoplatforms for TME modulation: From extracellular matrix to intracellular organelles

The tumor microenvironment (TME) plays a crucial role in aiding cancer progression and therapeutic resistance, this therefore necessitating innovative approaches for its effective modulation. This review aims to provide a comprehensive overview on the recent development and application of tumor responsive dynamic nanoplatforms for TME modification. We systematically analyzed extracellular TME modulation strategies, including modulation of tumor acidity, stroma remodelling, vascular normalization, stromal cell reprogramming, and temperature modulation. Additionally, we explored intracellular modulation techniques, including redox homeostasis modulation, metabolic reprogramming, energy supply modulation, and organelle targeted interventions. This detailed analysis revealed that traditional methods usually focus on either extracellular or intracellular modulation separately, each with its own set of limitations. For instance, extracellular modification alone often lacks direct cytotoxic effects, while intracellular targeting faces delivery barriers created by the extracellular matrix. Thus, the integration of both extracellular and intracellular TME reprogramming has been recommended as future therapeutic strategies to achieve better treatment outcomes. This review aims to offer a deeper understanding of current TME modulation approaches, highlighting key advancement and inspiring new ideas for creating more effective cancer treatments by comprehensively targeting and modifying the TME.