Tremendous efforts have been devoted to the enhancement of drug solubility using nanotechnologies,but few of them are capable to produce drug particles with sizes less than a few nanometers.This challenge has been addressed here by using biocompatible versatile γ-cyclodextrin （γ-CD) metal-organic framework (CD-MOF) large molecular cages in which azilsartan (AZL) was successfully confined producing clusters in the nanometer range.This strategy allowed to improve the bioavailability of AZL in Sprague-Dawley rats by 9.7-fold after loading into CD-MOF.The apparent solubility of AZL/CD-MOF was enhanced by 340-fold when compared to the pure drug.Based on molecular modeling,a dual molecular mechanism of nanoclusterization and complexation of AZL inside the CD-MOF cages was proposed,which was confirmed by small angle X-ray scattering (SAXS) and synchrotron radiation-Fourier transform infrared spectroscopy (SR-FTIR) techniques.In a typical cage-like unit of CD-MOF,three molecules of AZL were included by the γ-CD pairs,whilst other three AZL molecules formed a nanocluster inside the 1.7 nm sized cavity surrounded by six γ-CDs.This research demonstrates a dual molecular mechanism of complexation and nanoclusterization in CD-MOF leading to significant improvement in the bioavailability of insoluble drugs.