Engineering stimuli-responsive dendrimers for drug delivery: A 15-year review of formulation strategies and routes of administration

Over the last fifteen years, dendrimers as drug delivery systems have evolved from simple carrier systems to advanced, stimuli-responsive systems capable of modulating drug release in response to internal (e.g., pH, enzymes) and external (e.g., temperature, magnetic field) stimuli. Such advancements have made them highly promising for spatiotemporal control, enhanced therapeutic efficacy, and personalized medicine. - and multi-stimuli responsive dendrimers have attracted interest because they readily incorporate various natural or artificial triggers, enabling accurate and safe drug release in complex biological environments. These formulations have also contributed to modulating drug release after administration through various routes, including oral, transdermal, and relatively less explored routes such as buccal. Commonly used components in dendrimer-based formulations include drugs, dendrimers, solvents, ligands, nanoparticles as cores, and solubilizing agents. The aim of this review is therefore to critically analyse literature from the last 15 years that discusses various stimuli-responsive dendrimeric formulations studied across different routes of administration in drug delivery. It highlights various linker chemistries and surface engineering strategies used to control drug release in response to a stimulus. The review also examines how various routes of administration affect the release patterns and therapeutic performance of the formulation, thereby serving as a practical roadmap for researchers developing precision nanomedicines. Finally, the current drawbacks/limitations of stimuli-responsive dendrimers, including in vivo specificity, biocompatibility, scalability, reproducibility, and obstacles to clinical translation, are critically reviewed.