Polymeric nanoparticle formation is characterized by high risks of premature drug leaching and low drug encapsulation efficiency. This is aggravated by slow nanoparticle formation by large molecular weight polymers due to their slow diffusion kinetics in the reaction medium. This study investigated model protein drug insulin encapsulation by large molecular weight pectin and chitosan. The nanoparticles were prepared through pectin-chitosan coacervation and when necessary, together with pectin or chitosan crosslinking by calcium or tripolyphosphate ions in the same process. The formed particles were nanospray-dried when required. The size, zeta potential, morphology, drug content, drug association efficiency, polymer-polymer and drug-polymer interaction in particulate matrix were examined. The pectin-chitosan nanoparticles were able to encapsulate insulin substantially only if these nanoparticles were formed with rapid particle aggregation into micromatrices as a result of particle surfaces attracting the oppositely charged polymer chains via crosslinking as well as coacervation processes. The particulate aggregation level of micromatrices can be reduced via nanospray drying. Small discrete nanoparticles were obtainable from micromatrices. (C) 2014 Elsevier B.V. All rights reserved.