Among a variety of inorganic-based nanomaterials, mesoporous silica nanoparticles (MSNs) have several attractive features for application as a delivery system, due to their high surface areas, large pore volumes, uniform and tunable pore sizes, high mechanical stability, and a great diversity of surface functionalization options. We developed novel hybrid MSNs composed of a mesoporous silica nanostructure core and a pH-responsive polymer shell. The polymer shell was prepared by RAFT polymerization of 2-(diisopropylamino)ethyl methacrylate (pKa ~6.5), using a hybrid grafting approach. The hybrid nanoparticles have diameters of ca. 100 nm at pH < 6.5 and ca. 60 nm at pH > 6.5. An excellent control of cargo release is achieved by the combined effect of electrostatic interaction of the cargo with the charged silica and the extended cationic polymer chains at low pH, and the reduction of electrostatic attraction with a simultaneous collapse of the polymer chains to a globular conformation at higher pH. The system presents a very low (almost null) release rate at acidic pH values and a large release rate at basic pH, resulting from the squeezing-out effect of the coil-to-globule transition in the polymer shell.

Stimuli-responsive polymer materials are used in smart nanocarriers to provide the stimuli-actuated mechanical and chemical changes that modulate cargo delivery. To take full advantage of the potential of stimuli-responsive polymers for controlled delivery applications, these have been grafted to the surface of mesoporous silica particles (MSNs), which are mechanically robust, have very large surface areas and available pore volumes, uniform and tunable pore sizes and a large diversity of surface functionalization options. Here, we explore the impact of different RAFT-based grafting strategies on the amount of a pH-responsive polymer incorporated in the shell of MSNs. Using a “grafting to” (gRAFT-to) approach we studied the effect of polymer chain size on the amount of polymer in the shell. This was compared with the results obtained with a “grafting from” (gRAFT-from) approach, which yield slightly better polymer incorporation values. These two traditional grafting methods yield relatively limited amounts of polymer incorporation, due to steric hindrance between free chains in “grafting to” and to termination reactions between growing chains in “grafting from.” To increase the amount of polymer in the nanocarrier shell, we developed two strategies to improve the “grafting from” process. In the first, we added a cross-linking agent (gRAFT-cross) to limit the mobility of the growing polymer and thus decrease termination reactions at the MSN surface. On the second, we tested a hybrid grafting process (gRAFT-hybrid) where we added MSNs functionalized with chain transfer agent to the reaction media containing monomer and growing free polymer chains. Our results show that both modifications yield a significative increase in the amount of grafted polymer.

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Mild cognitive impairment (MCI) is characterized by cognitive, psychological, and functional impairments. Digital interventions typically focus on cognitive deficits, neglecting the difficulties that patients experience in instrumental activities of daily living (IADL). The global conjecture created by COVID-19 has highlighted the seminal importance of digital interventions for the provision of healthcare services. Here, we investigated the feasibility and rehabilitation potential of a new design approach for creating highly realistic interactive virtual environments for MCI patients’ neurorehabilitation. Through a participatory design protocol, a neurorehabilitation digital platform was developed using images captured from a Portuguese supermarket (NeuroVRehab.PT). NeuroVRehab.PT’s main features (e.g., medium-sized supermarket, the use of shopping lists) were established according to a shopping behavior questionnaire filled in by 110 older adults. Seven health professionals used the platform and assessed its rehabilitation potential, clinical applicability, and user experience. Interviews were conducted using the think-aloud method and semi-structured scripts, and four main themes were derived from an inductive semantic thematic analysis. Our findings support NeuroVRehab.PT as an ecologically valid instrument with clinical applicability in MCI neurorehabilitation. Our design approach, together with a comprehensive analysis of the patients’ past experiences with IADL, is a promising technique to develop effective digital interventions to promote real-world functioning.