Biodegradable cellulose photoacoustic probes are provided that are able to detect biological targets and generate a detectable photoacoustic signal. The cellulose nanoparticles are biodegradable by cellulases. Clearance of the nanoparticles from a subject is enhanced and results in improved contrast of a photoacoustic-generated image. Methods to generate images by administering a cellulose nanoparticle probes to a subject and irradiating with light of a wavelength to emit photoacoustic energy detectable by sensors external to the subject are also provided. The detectable signal is convertible to a visual image of the nanoparticle probes in the subject. The methods may include allowing a cellulase to degrade nanoparticles so that undesirable background signals emitted are substantially reduced to increase the contrast and quality of the generated image. In the absence of an endogenous source of an enzyme for degrading the cellulose nanoparticles, a composition comprising a heterologous cellulase may be administered along with the nanoparticles.
