Reprogramming the In Vivo Fate of Nanoassemblies: Morphology Regulation to Rod-Like Nanostructures to Enhance...

Nanodrug delivery systems show great potential in cancer therapy. However, conventional spherical nanoparticles are rapidly recognized and cleared by the mononuclear phagocyte system (MPS). This results in shortened circulation and inadequate tumor accumulation, which ultimately compromises the therapeutic efficacy. Previous studies have suggested that anisotropic morphologies, such as rod-like or worm-like nanostructures, can prolong blood circulation and promote tumor tissue-specific distribution. Nevertheless, controlling the morphology of nanoparticles without altering their chemical composition remains a significant challenge. In this study, we report a novel strategy for physical morphology regulation using prodrug nanoassemblies as a model. Specifically, this process refers to a noncovalent, energy-driven structural reorganization that proceeds without chemical bond cleavage or formation. An ultrasound-assisted one-step nanoprecipitation method is employed to controllably transform thioether-linked SN38 prodrugs (SN38-S-OA) from spherical nanoassemblies into highly uniform nanorods (NRs) with aspect ratios (AR) of 5 or 8. In contrast, the disulfide linkage provides more structural defects, which hinders similar structural reorganizations. Biological evaluations demonstrated that SN38-S-OA NRs AR5 achieved reduced macrophage uptake, prolonged blood circulation, enhanced tumor accumulation, and superior antitumor efficacy compared with those of SN38-S-OA NPs and SN38-SS-OA NPs. Additionally, an optimal aspect ratio is identified, as overly elongated SN38-S-OA NRs AR8 exhibited reduced tumor cell uptake due to increased steric hindrance. This study establishes purely physical morphology regulation as an independent design principle that prolongs circulation, enhances tumor targeting, and improves the therapeutic efficacy in nanomedicine.