Nanoparticles with tunable pharmacokinetics are desirable for various biomedical applications. Poly(ethylene glycol) (PEG) is well-known to create "stealth" effects to stabilize and extend the blood circulation of nanoparticles. In this work, poly(carboxybetaine) (PCB), a new nonfouling polymer material, was incorporated as surface-grafted coatings, conjugated onto degradable shell cross-linked knedel-like nanoparticles (dSCKs) composed of poly(acrylic acid)-based shells and poly(lactic acid) cores, to compare the in vivo pharmacokinetics to their PEG-functionalized analogues. A series of five dSCKs was prepared from amphiphilic block copolymers, having different numbers and lengths of either PEG or PCB grafts, by supramolecular assembly in water followed by shell cross-linking, and then studied by a lactate assay to confirm their core hydrolytic degradabilities. Each dSCK was also conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid macrocyclic chelators and tyramine moieties to provide for (64)Cu and/or radiohalogen labeling. The high specific activity of (64)Cu radiolabeling ensured nanogram administration of dSCKs for in vivo evaluation of their pharmacokinetics. Biodistribution studies demonstrated comparable in vivo pharmacokinetic profiles of PCB-grafted dSCKs to their PEG-conjugated counterparts. These results indicated that PCB-functionalized dSCKs have great potential as a theranostic platform for translational research.