Major challenges that confront nanoscience in medicine today include the development of efficacious therapies with minimum side effects, diagnostic methods featuring significantly higher sensitivities and selectivities, and personalized diagnostics and therapeutics for theragnostic approaches. With these goals in mind, combining biological molecules and synthetic carriers/templates, such as polymer supramolecular assemblies, represents a very promising strategy. In this critical review, we present protein–polymer systems as reaction spaces at the nano-scale in which the enzymatic reactions take place inside polymer supramolecular assembly, at its interface with the environment or in a combination of both. The location of the protein(s) with respect to the polymer assembly generates a diversity of systems ranging from nanoreactors to active enzymatic polymer surfaces. We describe these both in terms of general modelling and addressing the specific conditions and requirements related to the medical domain. We will particularly present protein–polymer nanoreactors that provide protected spaces for enzymatic reactions. We also show how polymer supramolecular structures, such as micelles, capsules, dendrimers and vesicles, can accommodate sensitive biomolecules to mimic natural systems and functions, and to serve as avenues for new medical approaches. Even though not yet on the market, we will emphasize possible applications of protein–polymer systems that generate reaction nanospaces—as novel ways to advanced medicine (264 references).

Antibodies recognizing complexes of the chemokine platelet factor 4 (PF4/CXCL4) and polyanions (P) opsonize PF4-coated bacteria hereby mediating bacterial host defense. A subset of these antibodies may activate platelets after binding to PF4/heparin complexes, causing the prothrombotic adverse drug reaction heparin-induced thrombocytopenia (HIT). In autoimmune-HIT, anti-PF4/P-antibodies activate platelets in the absence of heparin. Here we show that antibodies with binding forces of approximately 60–100 pN activate platelets in the presence of polyanions, while a subset of antibodies from autoimmune-HIT patients with binding forces ≥100 pN binds to PF4 alone in the absence of polyanions. These antibodies with high binding forces cluster PF4-molecules forming antigenic complexes which allow binding of polyanion-dependent anti-PF4/P-antibodies. The resulting immunocomplexes induce massive platelet activation in the absence of heparin. Antibody-mediated changes in endogenous proteins that trigger binding of otherwise non-pathogenic (or cofactor-dependent) antibodies may also be relevant in other antibody-mediated autoimmune disorders.

Neutrophils are immune cells that engage in a suicidal pathway leading to the release of partially decondensed chromatin, or neutrophil extracellular traps (NETs). NETs behave as a double edged sword; they can bind to pathogens thereby ensnaring them and limiting their spread during infection; however, they may bind to host circulating materials and trigger thrombotic events, and are associated with autoimmune disorders. Despite the fundamental role of NETs as part of an immune system response, there is currently a very poor understanding of how their nanoscale properties are reflected in their macroscopic impact. In this work, using a combination of fluorescence and atomic force microscopy, we show that NETs appear as a branching filament network that results in a substantially organized porous structure with openings with 0.03 ± 0.04 μm² on average and thus in the size range of small pathogens. Topological profiles typically up to 3 ± 1 nm in height are compatible with a “beads on a string” model of nucleosome chromatin. Typical branch lengths of 153 ± 103 nm appearing as rigid rods and height profiles of naked DNA in NETs of 1.2 ± 0.5 nm are indicative of extensive DNA supercoiling throughout NETs. The presence of DNA duplexes could also be inferred from force spectroscopy and the occurrence of force plateaus that ranged from ∼65 pN to 300 pN. Proteolytic digestion of NETs resulted in widespread disassembly of the network structure and considerable loss of mechanical properties. Our results suggest that the underlying structure of NETs is considerably organized and that part of its protein content plays an important role in maintaining its mesh architecture. We anticipate that NETs may work as microscopic mechanical sieves with elastic properties that stem from their DNA–protein composition, which is able to segregate particles also as a result of their size. Such a behavior may explain their participation in capturing pathogens and their association with thrombosis.