soft, core-shell cellulosic nanoparticles, for instance, to alter surface activity toward proteins, [4,5] remains largely untapped. Nanoparticles are generally synthesized by grafting soft polymeric structures onto rigid, rod-like nanocrystals, i.e., becoming hard-core/soft-shell nanoparticles. [6,7] This approach is rather time-consuming, especially if compared to cellulose II hydrogels. [8-10] Expanding on the latter, cellulose II nanospheres have been recently introduced through a facile and "green" avenue. [11,12] They consist of spherical nanocrystals [13-15] interconnected within a fibrillar network. [8-10,16] By installing repulsive charges onto the surface of cellulose II hydrogels, it is possible to develop functional cellulose II nanospheres with an intrinsic soft and amorphous shell. [11,12] This new class of cellulose colloids features the rheological and electrophoretic properties typical of soft particles as well as intraparticle and pH-responsive swelling behavior. The shells of the soft particles are anionic and can deform and interpenetrate [17-19] into a jammed colloidal nanogel. [12] Among the latter, classical supramolecular nanogels are defined as swollen nanosized networks of polymer chains [20] and are already used, for example, to control protein interactions. [21-24] Controlling these interactions is crucial in Soft cationic core/shell cellulose nanospheres can deform and interpenetrate allowing their self-assembly into densely packed colloidal nanogel layers. Taking advantage of their water-swelling capacity and molecular accessibility, the nanogels are proposed as a new and promising type of coating material to immobilize bioactive molecules on thin films and paper. The specific and nonspecific interactions between the cellulosic nanogel and human immunoglobulin G as well as bovine serum albumin (BSA) are investigated. Confocal microscopy, electroacoustic microgravimetry, and surface plasmon resonance are used to access information about the adsorption behavior and viscoelastic properties of self-assembled nanogels. A significant BSA adsorption capacity on nanogel layers (17 mg m −2) is measured, 300% higher compared to typical polymer coatings. This high protein affinity further confirms the promise of the introduced colloidal gel layer, in increasing sensitivity and advancing a new generation of substrates for a variety of applications, including immunoassays, as demonstrated in this work.