Controlling the biodistribution and clearance of nanomedicines

Nanomedicines improve drug bioavailability, the dose–response relationship, targeting ability, efficacy and safety compared to conventional freely administered drugs. Nonetheless, despite their success as carriers for SARS-CoV-2 vaccines, clinical use of nanomedicines is still limited, probably caused by mismatches between animal models and humans. In this Review, we propose that improving blood circulation, biodistribution and tissue accessibility could help improve the clinical translation of nanomedicines. Specifically, we emphasize control of the pharmacokinetics relevant to the administration route, therapeutic targets in tissues and cells, and the drug payloads. Furthermore, we analyse the clearance and distribution of nanomedicines in preclinical and clinical studies, highlighting the biological barriers determining their in vivo performance. Finally, we present engineering strategies, such as size tuning, active targeting for transcytosis, external stimuli and biological shifts, to overcome these barriers.