A platinum(<scp>iv</scp>)–crocetin nanoplatform with intracellular morphological transformation for enhanced colorectal cancer therapy

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy worldwide. Platinum(II)-based drugs, a cornerstone in CRC treatment, are often limited by significant side effects and suboptimal efficacy. Herein, we present a platinum(IV) prodrug nanoplatform (Pt(IV)-Cro NPs) designed to overcome these challenges through intracellular morphological transformation, enhancing therapeutic outcomes against CRC. Pt(IV)-Cro NPs are formed <i>via</i> the self-assembly of Pt(IV)-crocetin (Pt(IV)-Cro) and mPEG-crocetin (mPEG-Cro), driven by hydrophilic-hydrophobic interactions. These nanoparticles exhibit concentration-dependent morphology, transitioning from rod-shaped structures at lower concentrations to spherical forms at higher concentrations. Notably, Pt(IV)-Cro NPs undergo time-dependent morphological changes within cells. Upon uptake by CT26 cells, the nanoparticles retain a nanorod shape during the first hour but transform into spherical structures within 3 h. These morphological transitions contribute to a remarkable 141-fold reduction in the half-inhibitory concentration (IC₅₀) against CT26 cells compared to cisplatin alone. Pt(IV)-Cro NPs induced 3.14-fold greater apoptosis, 51.2% mitochondrial depolarization, and 55.9% ROS elevation compared to cisplatin. <i>In vivo</i> studies in CT26 tumor-bearing mice reveal that Pt(IV)-Cro NPs significantly outperform cisplatin alone, reducing tumor growth by up to 8.08 times relative to controls. This innovative nanoplatform combines enhanced efficacy with minimized side effects, offering a transformative approach to CRC therapy. The concentration-responsive self-assembly of Pt(IV)-Cro NPs and the occurrence of morphologic transformations within the cell characterize a major advancement in clinical CRC therapeutic strategies.