Covalent organic frameworks (COFs) as drug-delivery carriers have been mostly evaluated in vitro due to the lack of COFs nanocarriers that are suitable for in vivo studies. Here we develop a series of water-dispersible polymer-COF nanocomposites through the assembly of polyethylene-glycol-modified monofunctional curcumin derivatives (PEG-CCM) and amine-functionalized COFs (APTES-COF-1) for in vitro and in vivo drug delivery. The real-time fluorescence response shows efficient tracking of the COF-based materials upon cellular uptake and anticancer drug (doxorubicin (DOX)) release. Notably, in vitro and in vivo studies demonstrate that PEG-CCM@APTES-COF-1 is a smart carrier for drug delivery with superior stability, intrinsic biodegradability, high DOX loading capacity, strong and stable fluorescence, prolonged circulation time and improved drug accumulation in tumors. More intriguingly, PEG350-CCM@APTES-COF-1 presents an effective targeting strategy for brain research. We envisage that PEG-CCM@APTES-COF-1 nanocomposites represent a great promise toward the development of a multifunctional platform for cancer-targeted in vivo drug delivery.