Regulation of oxidative stress and inflammation caused by drug accumulation in the TME based on EPR-passive strategy and active targeting

Despite significant advancements in nanomaterials for cancer therapy, the clinical translation of cancer nanomedicine remains greatly hindered by insufficient accumulation of these nanomaterials within solid tumors—a critical bottleneck underlying the high failure rates observed in clinical trials. Our review systematically analyzes the mechanisms governing nanomaterial delivery to solid tumors, extending beyond the foundational Enhanced Permeability and Retention (EPR) effect. We critically evaluate passive strategies leveraging physicochemical properties (size switching, charge reversal) and tumor microenvironment (TME) modulation to amplify EPR-dependent delivery. Furthermore, we dissect active targeting paradigms—including ligand-directed, aptamer-based, and cell-mediated strategies, which exploit the distinct molecular and cellular characteristics of solid tumors to improve nanomaterial specificity and cellular uptake. Crucially, we highlight the bidirectional relationship between nanomedicine accumulation and TME dynamics, alongside the associated cytotoxic consequences. The review emphasizes the paradigm shift toward "passive–active" dual-targeting strategies and emerging technologies designed to overcome sequential physiological barriers. By integrating fundamental transport mechanisms, therapeutic efficacy, and toxicity profiles, this review offers a comprehensive framework for the rational design of next-generation nanomaterials with enhanced solid tumor accumulation and clinical applicability.