Burns are a global public health problem, which brings great challenges to public health and the economy.

Smart drug delivery, through which the drug molecules are delivered according to the requests of human biological rhythms or by maximizing drug therapeutic effects, is highly desired in pharmaceutics. Many biomacromolecules have been exploited for this application in the past few decades, both in industry and laboratories. Biphasic release, with an intentional pulsatile release and a following extended release stage, represents a typical smart drug delivery approach, which aims to provide fast therapeutic action and a long time period of effective blood drug concentration to the patients. In this study, based on the use of a well-known biomacromolecule, i.e., cellulose acetate (CA), as the drug (acetaminophen, ATP)-based sustained release carrier, a modified coaxial electrospraying process was developed to fabricate a new kind of core–shell nanoparticle. The nanoparticles were able to furnish a pulsatile release of ATP due to the shell polyvinylpyrrolidone (PVP). The time cost for a release of 30% was 0.32 h, whereas the core–shell particles were able to provide a 30.84-h sustained release of the 90% loaded ATP. The scanning electron microscope and transmission electron microscope results verified in terms of their round surface morphologies and the obvious core–shell double-chamber structures. ATP presented in both the core and shell sections in an amorphous state owing to its fine compatibility with CA and PVP. The controlled release mechanisms of ATP were suggested. The disclosed biomacromolecule-based process–structure–performance relationship can shed light on how to develop new sorts of advanced nano drug delivery systems.