Nanomedicines for resistant tumours in the central nervous system: novel materials and mechanisms of action

Central nervous system (CNS) tumours have a dismal prognosis, primarily due to the systemic therapeutic resistance that tumours develop through complex multidimensional networks. Factors related to therapeutic efficacy include: (i) natural physical barriers (e.g., the blood–brain barrier (BBB)) and the blood–brain tumour barrier, and cellular resistance mechanisms (e.g., efflux pumps, subcellular compartmentalisation, and metabolic inactivation)—which contribute to insufficient effective intracellular concentrations; (ii) molecular escape via DNA damage repair, target mutations, extrachromosomal DNA, and aberrant splicing; (iii) intrinsic drivers such as cancer stem cell dormancy, subtype switching, epigenetic remodelling, metabolic reprogramming, and resistance to multiple cell death modes; and (iv) microenvironmental factors (hypoxia, immunosuppression, and exosomes) alongside intertumoural neural-like physical networks and connections with host neurons, which ultimately facilitate shared toxicity and malignant regeneration. Nanomaterials enable potent sensitisation through the following multidimensional synergistic strategies: breaching the BBB and precisely targeting tumour cells to circumvent efflux pumps; co-delivering small-molecule inhibitors and nucleic acid drugs to silence resistance pathways; utilising physicochemical energy interventions to inhibit thermotolerant/drug-resistant proteins; and remodelling the microenvironment while switching apoptosis to novel death modes such as ferroptosis and pyroptosis. This article systematically reviews the application of five categories of nanomaterials—lipid-based, polymeric, inorganic, hybrid, and bioderived/biomimetic nanosystems—as methods to overcome drug resistance in CNS tumours, with a focus on analysing their inherent advantages, critical defects (e.g., carrier toxicity, in vivo stability, scale-up challenges, and clinical translation bottlenecks), and potential strategies for improvement. This paper aims to critically discuss the challenges and prospects of the clinical translation of various nanomaterials in reversing drug resistance, providing a reference for basic research and clinical practice.