A Neutral Single‐Molecule Carrier for Delivery of Phosphonate Drugs

Abstract Phosphate/phosphonate‐based drugs (PDs), as multinegative, hydrophilic molecules, face the greatest difficulty in diffusion across biological membranes, leading to poor bioavailability. Conventional drug delivery strategies to overcome this issue, including utilizing small‐molecule prodrugs or nanoparticle carriers, often suffer from case‐specific modifications or uncertainties in drug loading. Inspired by the anion coordination chemistry of natural phosphate transporters and artificial anion receptors, here, we present the first use of a neutral anion receptor, i.e., bis(tripodal hexaurea) cage 1 , as a “single‐molecule carrier” for the delivery of PDs into living cells. Cage 1 features advantages of molecular‐level encapsulation, enhanced intracellular accumulation, subcellular targeting, responsive drug release, and broad adaptability. It enhances PD accumulation in tumor cells both in vitro and in vivo, enhancing the cellular uptake of mono‐, di‐, and tri‐phosphate/phosphonate substrates by up to 45‐fold via a macropinocytosis‐mediated endocytosis pathway. This work demonstrates the potential of neutral anion receptors to serve as single‐molecule carriers and offers a promising solution for improving PDs bioavailability, advancing the development of antitumor phosphate/phosphonate‐based drugs.