Precision control of nanoparticle delivery with engineered biomimetic protein coronas

Abstract Nanoparticle delivery to tumors remains inefficient, with current nanomedicines achieving only 0.7% injected dose per gram (ID/g) of tumor tissue due to uncontrolled protein corona formation that redirects nanoparticles away from target sites. We engineered biomimetic protein coronas to control nanoparticle-protein interactions and enhance tumor targeting. Competitive binding studies using NMR spectroscopy revealed that transferrin (Tf) and fibronectin (Fn) outcompete albumin (BSA) and immunoglobulin G (IgG) for 15 nm gold nanoparticle surfaces, establishing a binding hierarchy that enables predictable corona composition. Pre-coating nanoparticles with a four-protein combination (BSA+Tf+Fn+IgG) created coronas that selectively enhanced cancer cell uptake while reducing macrophage recognition in vitro. When administered to tumor-bearing mice, these engineered coronas achieved 13 ppm/g tumor accumulation—equivalent to 4% ID/g—representing 6.5-fold improvement over bare nanoparticles and 2.6-fold improvement over PEGylated formulations. Proteomics analysis of secondary coronas formed in human serum revealed that engineered nanoparticles selectively recruit transport and adhesion proteins while limiting immune recognition signatures. The pre-formed coronas maintained targeting protein retention and reduced complement binding compared to controls. Circular dichroism confirmed minimal protein structural perturbation, preserving receptor-binding functionality for active targeting. The strategy harnesses natural protein adsorption processes to create “smart” biological interfaces that simultaneously evade immune clearance and promote tumor cell recognition through multiple receptor pathways. This approach demonstrates the feasibility of treating the coron as a programmable interface, addressing delivery limitations that have hindered clinical translation of cancer nanomedicines. For Table of Contents Only