Controlling nanoparticle targeting: from physicochemical design to molecular recognition

Nanomedicine has revolutionized drug delivery, providing innovative nanodelivery platforms that enhance biodistribution, targeting, precision, and therapeutic efficacy across a wide range of pathological conditions. The design of nanoparticles involves integrating physicochemical and biopharmaceutical properties, such as size, shape, and surface and interfacial characteristics, with delivery mechanisms associated with cell and tissue pathophysiology, or presence of specific macromolecules targetable with affinity ligands. Stimuli-responsive platforms are proving useful for precision, personalized medicine by exploiting the distinctive features of pathological tissues, including disease-dependent differences in pH, redox state, protease and other enzyme activity, and tissue microenvironment oxygenation to control the release of therapeutic payloads, thereby improving the therapeutic window and efficacy. Dynamic phenomena, such as protein corona formation and the immune system activation in response to nanoparticles, may represent both limitations and opportunities, as exemplified by macrophage hitchhiking of nanoparticles to improve therapeutic targeting. Here, we critically examine the main targeting strategies for nanoparticle design and functionalization, discussing advantages, limitations, and translational potential of different approaches and platforms.