Abstract
Nanoparticles have been widely used in tumor targeted drug delivery, while the antitumor effects are not always satisfactory due to the limited penetration and retention. As we all know, there is a paradox that nanoparticles with large sizes tend to distribute around tumor blood vessels rather than penetrate into tumor parenchyma, while smaller sizes can penetrate deeply but with poor tumor retention. In recent days, an intelligent, size-tunable strategy provided a solution to determine the size problem of nanoparticles and exhibited good application prospects. In this review, we summarize series of stimuli-induced aggregation and shrinkage strategies for tumor targeted drug delivery, which can significantly increase the retention and penetration of nanodrugs in tumor sites at the same time, thus promoting treatment efficacy. Internal (enzymes, pH, and redox) and external (light and temperature) stimuli are introduced to change the morphology of the original nanodrugs through protonation, hydrophobization, hydrogen bond, π-π stacking and enzymolysis-resulted click reactions or dissociation, etc. Apart from applications in oncotherapy, size-tunable strategies also have a great prospect in the diagnosis and real time bioimaging fields, which are also introduced in this review. Finally, the potential challenges for application and future directions are thoroughly discussed, providing guidance for further clinical transformation.