The convergence of nanotechnology and precision medicine has catalyzed the development of sophisticated smart drug delivery systems (SDDS) capable of delivering therapeutic agents with unprecedented specificity and spatiotemporal control. Unlike conventional drug delivery approaches, SDDS exploit disease-specific microenvironmental cues—including aberrant pH gradients, elevated glutathione levels, overexpressed enzymes, and hypoxic conditions—alongside externally applied stimuli such as light, temperature, and magnetic fields, to achieve on-demand payload release at the target site. This review aims to provide a comprehensive and critical appraisal of the current landscape of smart nanocarrier-based delivery platforms, including polymeric nanoparticles, liposomes, solid lipid nanoparticles, mesoporous silica nanoparticles, dendrimers, and emerging bio-inspired exosome-based carriers. Key stimuli-responsive and ligand-mediated targeting strategies are examined in the context of their mechanistic underpinnings and translational relevance. Major therapeutic applications discussed encompass targeted oncology, antimicrobial therapy for drug-resistant infections, management of chronic metabolic disorders, and genomic medicine encompassing siRNA and CRISPR-based therapeutics. Despite remarkable progress, challenges surrounding clinical translation—including manufacturing scalability, in vivo stability, immunogenicity, and regulatory approval pathways—remain formidable. This review concludes that the rational integration of smart delivery technologies with the genomic and biomarker profiling paradigms of precision medicine holds transformative potential for individualized patient care, and that emerging innovations in artificial intelligence-guided nanoparticle design and multifunctional theranostic platforms will define the next frontier of nanomedicine.