LAUSR

Surface functionalization of nanoparticles with polyethylene glycol (PEG) has been widely demonstrated as an anti-opsonization strategy to reduce protein corona formation which is one of the major concerns affecting target receptor recognition. However, excessive surface passivation with PEG can lead to the strong inhibition of cellular uptake and less efficient binding to target receptors, resulting in reduced potential of targeted delivery. To improve specific cell targeting while reducing the nonspecific protein adsorption, a secondary packaging of the nanoparticles with shorter PEG chains, making the targeting ligands densely stretched out for enhanced molecular recognition is demonstrated. Particularly, we report the tailored surface functionalization of the porous nanoparticles that require the stealth shielding onto the open-pore region. This study shows that, in addition to the surface chemistry, the conformation of the PEG layers controls the cellular interaction of nanoparticles. Since the distance between neighboring PEG chains determines the structural conformation of the grafted PEG molecules, tailored PEG combinations can efficiently resist the adsorption of serum proteins onto the pores by transitioning the conformation of the PEG chains, thus significantly enhance the targeting efficiency (>5-fold). The stretched brush PEG conformation with secondary packaging of shorter PEG chains could be a promising anti-opsonization and active targeting strategy for efficient intracellular delivery of nanoparticles.