The protein corona on nano drug carriers is an important well-known biological issue that often induces biological incompatibility and screens the targeting molecules on the surfaces of carriers, thus causing a loss of targeting specificity. Although polyethylene glycol (PEG) and zwitterionic polymers have been widely used as anti-fouling materials, there still remain critical challenges for their use as protein-corona agents for drug delivery and targeting. Here, we have designed novel amphoteric natural starch-stabilized core-shell colloidal nanoparticles with more efficient protein corona-free properties, under long term circulation, at different protein concentrations and in different protein charge environments, compared to typical anti-fouling materials such as PEG and zwitterionic polymers. More importantly, the starch-coated polymer nanoparticles can be further functionalized by antibodies to achieve additional excellent targeting and cell internalization capabilities for their use in photodynamic therapy. Our findings demonstrate a novel protein-free or anti-fouling natural material that is very promising for use as highly efficient nano drug carriers and marine coatings.