Targeted Drug Delivery by Smart Nanocarriers: Design, Therapeutic and Their Translation Challenges

Abstract

Smart nanocarriers have become revolutionary delivery platforms in targeted drug delivery due to the critical vulnerabilities of traditional methods of therapeutic delivery, such as low bioavailability, non-specific delivery, and off-target toxicity. This review will discuss the rational design, therapeutic strategies and the translational issues of stimuli-responsive nanocarrier systems that are developed to obtain spatiotemporal control of drug release. The use of organic (liposomes, dendrimers, polymeric micelles), inorganic (gold, silver, iron oxide, graphene derivatives) and high-order hybrid (lipid-polymer hybrids, cell membrane-coated biomimetic systems) nanoparticles is discussed. Principles of nanocarrier design, such as the mechanics of physicochemical properties (size, shape, surface charge), targeting (passive EPR effect, active ligand-mediated recognition), and stimulus-responsive mechanisms (endogenous (pH, enzymes, redox)) or exogenous (temperature, light, magnetic field) stimuli are critically discussed. The therapeutic uses include oncology, where nanocarriers overcome the multidrug resistance and the tumor microenvironment, infectious disease, neurological diseases, cardiovascular diseases and inflammatory/autoimmune disorders. Although there has been considerable preclinical advancement and more than 4,000 clinical trials, there are still translational challenges, such as formation of protein corona, reticuloendothelial clearance, scale of manufacturing, regulatory complexity and issues related to immunogenicity. New paradigms, which combine artificial intelligence-based design, microfluidic organ-on-chip devices and patient-specific computational modeling, have the potential to overcome these obstacles. This review offers a platform upon which a rational design of future smart nanocarriers can be attained by integrating progress in nanomaterial engineering with biological and regulatory factors to achieve the potential of precision nanomedicine.