Design of disintegrable nanoassemblies to release multiple small-sized nanoparticles

The therapeutic and diagnostic effects of nanoparticles highly depend on the efficiency of their delivery to targeted tissues, such as tumors. The size of nanoparticles, among other characteristics, plays a crucial role in determining their tissue penetration and retention. Small nanoparticles may penetrate deeper into tumor parenchyma but are poorly retained, whereas large ones are distributed around tumor blood vessels. Thus, compared to smaller individual nanoparticles, assemblies of such nanoparticles due to their larger size are favorable for prolonged blood circulation and enhanced tumor accumulation. Upon reaching the targeted tissues, nanoassemblies may dissociate at the target region and release the smaller nanoparticles, which is beneficial for their distribution at the target site and ultimate clearance. The recent emerging strategy that combines small nanoparticles into larger, biodegradable nanoassemblies has been demonstrated by several groups. This review summarizes a variety of chemical and structural designs for constructing stimuli-responsive disintegrable nanoassemblies as well as their different disassembly routes. These nanoassemblies have been applied as demonstrators in the fields of cancer therapy, antibacterial infection, ischemic stroke recovery, bioimaging, and diagnostics. Finally, we summarize stimuli-responsive mechanisms and their corresponding nanomedicine designing strategies, and discuss potential challenges and barriers towards clinical translation.