ENHANCE: Engineering of nanoparticles by harnessing the biomolecular corona for cancer therapy

Nanomedicine promises to improve the diagnosis of diseases and the specificity of treatments, as well as the quality of life of patients during treatments. However, the current poor clinical translation of therapeutic nanotechnologies stems, among other reasons, from overlooking several factors of the nano-bio interface[1-2]. The unpredictable and uncontrollable adsorption of biomolecules on the surface of nanoparticles (NPs) upon exposure to biological fluids, creating the so-called protein corona, is an unavoidable process that strongly affect the trafficking of NPs into tissues, i.e., recognition by the immune system, blood circulation time, biodistribution, and endocytosis[3-15]. Adsorbed biomolecules may promote recognition and elimination of NPs by the immune system, acting as opsonins, or may reduce or inhibit phagocytic uptake, promoting the "stealth" effect of NPs, if they act as dysopsonins[1, 16-17]. It follows that the protein corona can be exploited to develop engineered NPs with improved delivery abilities (targeting and circulation). ENHANCE aims to radically change the current design and engineering paradigm of nanomedicine, moving from a physicochemical perspective to a biological outcome-driven perspective and making the protein corona an integral part of the engineering process. ENHANCE will develop engineered NPs that, through the rational design and manipulation of the protein corona, efficiently target colorectal cancer (CRC) and enhance the delivery of therapeutic monoclonal antibodies. The rational design of the protein corona will aim to both minimize the recognition of NPs by immune cells, by enriching dysopsonins or mitigating the adsorption of opsonins, and promote CRC cell targeting through the enrichment of proteins that favor the uptake of NPs. Since rational design of the protein corona requires the correlation between the properties of NPs and their biological effects, ENHANCE will employ gold and silver NPs to ensure: (i) availability of synthetic strategies with high control of morphological (size and shape) and surface properties; (ii) excellent chemical stability; and (iii) well known surface-chemistry[18-22]. As shown in figure 1, the engineering process of NPs will be guided by the analysis of the biological outcomes at different and increasing levels of complexity, moving from immune cells to 3D “in vitro” cell cultures and 3D “ex vivo” patient-derived models. As an important complementarity of experiments, ENHANCE will take advance from computational (in silico) tools to have both a deeper understanding of nanoparticle-biosystem interactions at the nano-bio interface and for experimental data analysis.[23] The approach envisioned will be of general applicability to the application of NPs in medicine and the long-term goal of this proposal is to provide a new paradigm for designing NPs for patient- and tissue-specific delivery and for minimizing adverse side effects.