While poly(acyclic orthoesters) (PAOEs) have many appealing features for drug delivery, their application is significantly hindered by a lack of facile synthetic method. Here we report a simple method for synthesizing acyclic diketene acetal monomers from diols and vinyl ether, and their polymerization with a diol to first synthesize PAOEs. The PAOEs rapidly hydrolyzed at lysosomal pH. With the help of a cationic lipid, ovalbumin, a model vaccine antigen, was efficiently loaded into PAOEs nanoparticles using a double emulsion method. These nanoparticles efficiently delivered ovalbumin into the cytosol of dendritic cells and demonstrated enhanced antigen presentation over PLGA nanoparticles. PAOEs are promising vehicles for intracellular delivery of biopharmaceuticals and could increase the utility of poly(orthoesters) in biomedical research.