Inorganic nanomedicines responsive to the tumor microenvironment: design strategies and functional integration

Abstract

The tumor microenvironment (TME) is a dynamic biochemical environment that controls how tumors grow, spread, and respond to treatment. Endogenous TME characteristics, including acidity, redox imbalance, enzyme dysregulation, hypoxia, and abnormal nucleic acid expression, constitute a multidimensional signaling network that encodes disease-specific information. Using these signals to selectively activate therapies has become a major idea in precision nanomedicine. Inorganic nanomaterials provide a versatile platform for decoding signals and transforming them into programmable therapeutic responses due to their structural robustness, adjustable physicochemical properties, and inherent catalytic and imaging capabilities. Nonetheless, the majority of contemporary systems are constrained by single-signal dependence, insufficient specificity, and inadequate adaptability to tumor heterogeneity. In this review, we characterize TME-responsive nanomedicines as signal-processing systems that include signal encoding, transduction, and functional output. We summarize the molecular origins of key endogenous signals and corresponding material design strategies, such as bond cleavage, physicochemical transformation, catalytic activation, and structural reconfiguration. We also describe how single-stimulus designs have changed into multi-stimuli logic-gated nanoplatforms that can make programmable therapeutic decisions. Lastly, we discuss the main problems and future paths for inorganic nanomedicines that can adapt, are based on logic, and can be used in clinical settings.