Rational Design of Amphiphilic Copillar[5]arene Conjugates for Enhanced Nanodelivery: Synthesis, Nanoparticle Optimization, and In Vitro Biocompatibility.

A single component, synthetically tunable amphiphilic copillar[5]arene platform was developed as a modular supramolecular scaffold for therapeutic nano-delivery. Structural variation of the hydrophobic segment, together with PEG functionalization, enables precise control over amphiphilicity, self-assembly, and host-guest behavior, thereby providing a single-component platform that addresses the multicomponent formulation challenges commonly associated with drug delivery systems. Notably, the hydrophobic and electron-rich cavity efficiently assisted in encapsulating a hypoxia-activatable self-immolative linker-based guest, highlighting the potential of this system for encapsulating therapeutically relevant cargos and enabling tumor-selective release. In Vitro studies further demonstrated efficient cellular uptake and negligible toxicity of the blank nanoformulation, validating its suitability as a delivery vehicle. This work establishes copillar[5]arene nano-assemblies as a versatile and synthetically tailorable suprascaffold that combines structural programmability, cargo compatibility, and biological safety, thereby providing a promising platform for precision cancer nanomedicine and advanced drug delivery applications.