Prodrug design represents a successful strategy to improve the biopharmaceutical properties of the drug released in the body, to obtain optimal therapeutic efficacy or provide new treatments or treatments with new indications or combinatory therapies with additive or synergistic properties. Nanomedicine is an emergent, effective strategy to optimize bioavailability, and it constitutes an exciting platform for the future of medicine. The combination of these two approaches, as evidenced by the increasing number of publications, represents a revolutionary rationale for the development of smart therapies, particularly against cancer and inflammation-related diseases, as well as the opportunity to overcome physiological barriers, including the blood-brain barrier. Two kinds of nanoplatforms can be settled, the first category is represented by nanoparticles obtained by the self-assembling properties of the amphiphilic prodrugs, while the second is exemplified by nanoparticles loaded with the prodrugs. Both strategies overcome typical limitations of the prodrugs, principally represented by a premature liberation of the drug with consequent early metabolism and reduced activity. Their nanocarrier encapsulation can prolong half-lives, improve site targeting, and enhance intracellular transport, even if premature drug leakage with a consequent burst effect and low drug loading capacity could occur and limit their use. Nanocarriers made of self-assembled prodrugs are free of excipients, with a consequent high drug loading. Sustained drug release at the targeted site is also an advantage, even if drug release dynamics can impart difficulties in optimizing the carrier.
