Multifunctional Hybrid Nanomedicines for Neurodegenerative Diseases: A Paradigm Shift from Rational Design to...

Effective drug delivery to the central nervous system remains a persistent challenge owing to the blood-brain barrier (BBB), heterogeneous pathological microenvironments, and the limited capacity of conventional carriers to achieve precise spatiotemporal control over drug release. Multifunctional hybrid nanomedicines (MHNs), defined here as engineered nanosystems that integrate two or more functional modules, such as targeted delivery, controlled release, and/or theranostic capabilities within a single platform, offer a transformative approach to neurotherapeutic design. This review traces the evolution of MHNs from passive carriers to stimuli-responsive, "smart" delivery platforms and presents a unified design framework built upon four synergistic strategies: (1) surface engineering for receptor-mediated BBB transcytosis and site-specific accumulation; (2) biomimetic surface modification to prolong systemic circulation and evade immune-mediated clearance; (3) controlled release systems responsive to endogenous stimuli (pH, redox gradients, pathologically elevated metal ions) or exogenous triggers (light, magnetic fields), with particular emphasis on metal-coordination bonds as tunable, microenvironment-sensitive release switches; and (4) theranostic integration enabling image-guided drug delivery and real-time therapeutic monitoring. The construction strategies, synergistic mechanisms, mechanistic principles, and therapeutic functions underpinning these four approaches are systematically examined in the context of neurodegenerative diseases. The current clinical translation landscape corresponding to each approach is also comprehensively surveyed. Furthermore, while most integrated MHN platforms remain at the preclinical stage, the principal challenges confronting MHNs are critically assessed, and prospective development trajectories associated with each approach are identified and discussed, thereby providing a substantive reference framework for the next-generation design of MHNs with effective spatiotemporal controlled release capabilities.