Nanoscale. 2025 Mar 05.
Biological barriers significantly impede the delivery of nanotherapeutics to diseased tissues, diminishing therapeutic efficacy across pathologies such as cancer and inflammatory disorders. Although conventional strategies integrate multifunctional designs and molecular components into nanomaterials (NMs), many approaches remain insufficient to overcome these barriers. Key challenges, including inadequate drug accumulation at target sites and nonspecific biodistribution, persist in nanotherapeutic development. NMs, which harness the ability to precisely modulate drug delivery spatiotemporally and control release kinetics, represent a transformative platform for targeted cancer therapy. In this review, we highlight the biological obstacles limiting effective cancer treatment and evaluate how stimuli-responsive NMs address these constraints. By leveraging exogenous and endogenous stimuli, such NMs improve therapeutic specificity, reduce off-target effects, and amplify drug activity within pathological microenvironments. We systematically analyze the rational design and synthesis of stimuli-responsive NMs, driven by advances in oncology, biomaterials science, and nanoscale engineering. Furthermore, we highlight advances across NM classes-including polymeric, lipid-based, inorganic, and hybrid systems and explore functionalization approaches using targeting ligands, antibodies, and biomimetic coatings. Diverse delivery strategies are evaluated, such as small-molecule prodrug activation, peptide- and protein-based targeting, nucleic acid payloads, and engineered cell-mediated transport. Despite the promise of stimuli-responsive NMs, challenges such as biocompatibility, scalable fabrication, and clinical translation barriers must be addressed. By elucidating structure-function relationships and refining stimulus-triggered mechanisms, these NMs pave the way for transformative precision oncology strategies, enabling patient-specific therapies with enhanced efficacy and safety. This synthesis of interdisciplinary insights aims to catalyze innovation in next-generation nanomedicine for cancer treatment.