It is increasingly evident that tumor-associated macrophages (TAMs) play an important role in tumor invasion, proliferation, and metastasis. While delivery of drugs, imaging agents, and vaccines to TAMs was achieved by exploiting membrane receptors on TAMs, the uptake by normal macrophages remains an issue. In this communication, we report a PEG-sheddable, mannose-modified nanoparticle platform that can efficiently target TAMs via mannose-mannose receptor recognition after acid-sensitive PEG shedding in the acidic tumor microenvironment, while their uptake by normal macrophages in the mononuclear phagocyte system (MPS) organs was significantly reduced due to effective PEG shielding at neutral pH. These nanoparticles have the potential to target drugs of interest to TAMs, with decreased uptake by normal macrophages.