Nanocarrier strategies for deep tumour penetration

Abstract

Deep penetration of nanocarriers into solid tumours remains a major obstacle in cancer nanomedicine due to the complex tumour microenvironment (TME) and associated physiological barriers. This review provides a comprehensive analysis to guide the design of stimuli-responsive nanocarriers capable of overcoming these transport limitations and enhancing therapeutic efficacy. It begins by examining key nanocarrier classes, including lipid-based, polymeric, inorganic, biomacromolecular, and hydrogel systems, highlighting their structural features, advantages, and limitations. Special focus is given to charge-reversal nanoparticles, which leverage TME-specific triggers such as acidic pH, redox gradients, and enzymatic activity to enhance tumour infiltration and cellular uptake. The review also evaluates complementary strategies including size and shape transformation, surface ligand modification, propulsion-based delivery, and pharmacological modulation of the TME. Collectively, these approaches offer a promising framework for engineering nanocarrier systems capable of targeted delivery, enhanced tumour penetration, and precise spatiotemporal control of drug release.