Autonomous intranasal delivery systems for central nervous system therapeutics

Intranasal delivery provides a rapid, non-invasive route to the central nervous system, bypassing the blood-brain barrier and first-pass metabolism. However, its therapeutic potential remains constrained by the nasal cavity's complex anatomy, the restricted surface area and permeability of the olfactory epithelium, and short drug residence times. Recent advances in nanotechnology and synthetic biology have enabled the development of autonomous and programmable delivery systems that can target the olfactory epithelium, enhance brain entry and sustain therapeutic release. This review highlights current strategies for engineering intranasal drug delivery vectors that can replicate or extend cellular functions to enable autonomous nose-to-brain drug delivery. These vectors include: synthetic nanoparticles that mimic essential cellular activities and allow for modular surface modification; extracellular vesicles that naturally carry therapeutic cargo and exhibit parent-cell-derived tropism; and living therapeutics, such as engineered microbes, viruses or stem cells, that respond dynamically to host environments and can be genetically programmed for precise payload production. Emphasis is placed on the modular design of functional components, host-responsive interactions tailored to anatomical and physiological cues, and the integration of programmable functions that collectively drive delivery autonomy and therapeutic efficacy. Together, these advances position intranasal delivery as a versatile platform for treating neurological disorders, offering a foundation for future translational development.