Abstract <p>Typical drug administration methods are often limited by low bioavailability, lack of specificity in biodistribution, rapid systemic clearance and dose-dependent toxicity, which adversely impact both the therapeutic efficacy and safety of the patient. Nanoparticle-based drug delivery systems have been heralded as potential solutions to various challenges that are simply inherent in conventional methods of drug treatment, for instance, the capacity to administer drugs in a controlled release manner, enhancing stability and targeted delivery to very specific sites. In this review, a more detailed and in-depth discussion of the different categories of nanoparticle systems will be presented. For example, organic nanoparticles (liposomes, polymeric nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers and nanoemulsions), inorganic nanoparticles (iron oxide nanoparticles, quantum dots and gold nanoparticles) and hybrid systems that integrate multifunctional design features. Besides, the various mechanisms through which targeted delivery is achieved have been very thoroughly brought up in the paper. These mechanisms are passive targeting via the enhanced permeability and retention (EPR) effect, active ligand-mediated targeting through receptor-ligand interactions and also, pH, redox, enzyme, temperature and external field stimuli responsive systems. Various important synthesis methods include nanoprecipitation, high-pressure homogenization, microfluidics and green synthesis while some of the important characterization methods entail dynamic light scattering, electron microscopy, zeta potential analysis and drug loading efficiency analysis. In addition to descriptive classification, other translational factors such as scalability, batch reproducibility, protein corona formation, biodistribution variability, long-term safety and regulatory issues that affect clinical applicability are highlighted in this review. Although, a few nanoparticle formulations have been allowed by regulatory bodies, numerous potential platforms are limited by the challenge of the complexity of manufacturing and poor consistency in vivo. The future outlooks point at the necessity of standardized characterization schemes, enhanced predictive in vivo protocols, incorporation of precision medicine schemes and rational design schemes that would compromise between multifunctionality and clinical attainability. It will not be possible to generalize the use of nanoparticle-based drug delivery without not only innovative material engineering but also a realistic correspondence with biological and regulatory constraints to provide meaningful therapeutic translation. This review summarizes the recent developments that are recorded mainly within the 2018–2025 period, with notable changes in the priorities of assessing translational effectiveness, regulation and design of nanoparticles.</p> Lay Summary <p>Nanoparticles and nanomaterials have restructured the arena of targeted drug delivery to provide unprecedented manipulation of drug localisation, release kinetics and intracellular fate. The ability of their tunable properties, size, shape, charge and surface functionality and responsiveness to biological or external cues, allows them to surmount most of the inherent constraints of traditional therapeutics.</p> Graphical Abstract <p></p>