Supra‐Hybrid Nanocarriers of Calix[4]Arene and PLGA for Enhanced Encapsulation and Extended Delivery of Gossypol in Cancer Therapy

Abstract In this study, supra‐hybrid nanocarriers Cal‐P NPs are developed by combining amphiphilic macrocyclic calix[4]arene and PLGA, offering adequate stability and multifunctionality as a single‐platform nanocarrier resulting in monodispersed nanoparticles with unique synthetic tunability and an optimized hydrophobic core for therapeutic encapsulation. Unlike conventional multicomponent systems, the design eliminates the need for many external stabilizers while enabling tailored PEGylation for controlled drug release, as demonstrated with hydrophobic gossypol. This innovation addresses key limitations in cancer nanomedicine, including premature drug leakage and dose frequency, through a synthetically tunable and structurally optimized, bioresistant core. Gossypol, a model bioactive molecule with poor water solubility, is effectively loaded into the Cal‐P NPs, significantly enhancing its aqueous solubility to millimolar concentrations. The encapsulation is driven by favorable interactions between gossypol and the hydrophobic groups of calixarene and PLGA, resulting in a stable core with sustained release properties. Validated through in vivo pharmacokinetic studies and detailed anticancer experiments in two distinct cancer cell lines, GP‐Cal‐P NPs demonstrated their potential as a robust platform for therapeutic delivery. These findings emphasize the versatility of Cal‐P NPs in addressing challenges associated with hydrophobic drugs and highlight their promise for further preclinical and clinical development.