The new concept of modifying and tailoring the properties of existing two-dimensional (2D) nanomaterials by invoking the assembly of supramolecular networks upon association with a adenine-functionalized macromer (A-PPG) has significant potential to facilitate the development of highly water-dispersible few-layered 2D nanosheets. In this study, we propose that water-soluble A-PPG directly self-assembles into a long-period stacking-ordered lamellar structure over the surface of hexagonal boron nitride (BN) in aqueous solution, due to the efficient non-covalent interactions between A-PPG and BN nanosheets. The layer number of BN nanosheets can be easily tuned by altering the mass ratio of the A-PPG and BN blend, and the resulting exfoliated nanosheets also exhibit excellent temperature/pH-responsive behavior, biocompatibility and extremely high drug-loading capacity (up to 36.2%), features that are highly desirable yet exceedingly rare in traditional 2D nanomaterials. Importantly, in vitro drug release studies showed the drug-loaded nanosheets function as a stable nanocarrier with excellent stability and drug entrapment under normal physiological conditions. Increasing the environmental temperature to 40 °C or decreasing the pH to 5.5 triggered rapid release of the encapsulated drug from the drug-loaded nanosheets, suggesting this newly developed material has potential as a novel multi-responsive 2D nanocarrier to safely deliver drugs and effectively facilitate controlled drug release under specific microenvironmental conditions. This study provides new insight towards the promising application of this system in controlled release drug delivery systems.