Nanomaterial-based drug delivery systems (NDDS) have become enabling technologies for small-molecule reformulation, RNA medicines, vaccines, gene editing, immunotherapy, and regenerative therapeutics. Their clinical performance, however, is determined not only by cargo loading and release but also by protein-corona evolution, immune recognition, biological-barrier navigation, intracellular trafficking, manufacturing control, and regulatory fit. This review provides a cross-platform comparison of lipid nanoparticles, polymeric nanoparticles, inorganic nanomaterials, extracellular vesicles (EVs), and biomimetic nanocarriers with respect to cargo compatibility, targeting potential, circulation behavior, scalability, clinical maturity, and regulatory status. Passive, active, biomimetic, and organ-selective targeting strategies are critically compared, and recent advances in extrahepatic lipid nanoparticle delivery, biodegradable ionizable lipids, programmable polymers, EV manufacturing, and nano-bio interactions are evaluated. We further integrate disease applications with quantitative lessons from approved products and representative clinical attrition, and compare regulatory expectations across major US, European, Japanese, Chinese, and ICH frameworks. Emerging computational approaches—including high-throughput screening, machine-learning-guided material discovery, autonomous formulation laboratories, generative design, and digital twins—are discussed alongside their validation requirements. A structured translational roadmap is proposed that prioritizes biologically predictive design, fit-for-purpose safety assessment, scalable good manufacturing practice production, early regulatory alignment, and clinically meaningful benefit over unnecessary structural complexity.