Polymeric nanoparticles are promising carriers for the delivery of chemotherapeutics for cancer therapy because they are able to carry large payload of therapeutic modality, extravasate leaky tumor vasculature, and mediate sustained drug release in tumor tissues. Of a handful of nanoparticulate carriers being studied, polymeric nanoencapsulates are particularly promising because they can be readily prepared through the co-precipitation of hydrophobic polymers and small molecule drugs in a process called nanoprecipitation. However, nanoencapsulates typically have significant drug burst release, low drug loading and uncontrollable drug encapsulation efficiency. To address these issues, we developed nanoconjugation technique to allow successful formulations of sub-100 nm sized, mono-modal nanoconjugates with definable drug loading, quantitative drug loading efficiency and controlled release profiles. Nanoconjugates were prepared through a drug-initiated ring opening polymerization followed by nanoprecipitation. In the first step, hydroxyl-containing therapeutic agents are used as initiators to initiate living polymerization of cyclic ester monomers (e.g.,lactide), and result in polyester-therapeutics conjugates. In the second step, precipitation of the polyester-therapeutics conjugates gives the desired polyester-drug nanoconjugates. Using paclitaxel as a model drug, we have been able to formulate paclitaxel-polylactide nanoconjugates with 100% drug incorporation efficiency and up to 37% drug loading. This new type of nanoparticles is promising delivery vehicle for targeted cancer therapy with improved efficacy and reduced toxicity.