## 4 Nanostructured Systems for Immunotherapeutic Delivery in Non- Malignant Applications
### Infectious Diseases
As illustrated in Figure 7, these materials facilitate antigen delivery via improved uptake by Antigen Presenting Cells (APCs), such as neutrophils, macrophages, and dendritic cells. Once internalized via endocytosis, the antigens are processed through proteasome complexes and presented via major histocompatibility complexes (MHC) on the surface of APCs. This process triggers the activation of both CD8+ cytotoxic T cells and CD4+ helper T cells, promoting a strong adaptive immune response. Helper T cells further aid in the differentiation of memory B cells and plasma cells, resulting in the production of antigen-specific antibodies. These benefits are correlated to the particles' extremely small size, making it easier for APCs to internalize them, allowing for effective antigen recognition, and boosting the overall vaccine efficacy [120; 121]. Figure 6: Schematic representation of immunotherapy as a potential treatment for patients with infectious disease. Reprinted from an open-access source [119]. Moreover, these nanomaterials can be surface-functionalized with different targeting moieties, enabling the precise transport of antigens to specific receptors on the cell surface producing selective and specific immune responses [120]. An interesting example of surface-modified nanoparticles for vaccine formulations has been reported by [PERSON] and colleagues [136]. The authors developed a dual-polymer modified GO (GO-PEG-PEI) vaccine adjuvant for immunotherapy using urease B (Ure B), an antigen specific to _Helicobacter pylori_. The proposed nanostructured system was found to enhance dendritic cell maturation and cytokine secretion through TLR pathways while effectively delivering antigens, and inducing a stronger cellular immunity compared to free Ure B and aluminum-adjuvant vaccines. Therefore, the study highlights the importance of surface chemistry in nano-adjuvant design. Differently, [PERSON] et al. [137] explored the possibility of nasal vaccination that generates humoral and cellular immune responses. The researchers employed a nanocarrier comprising a hydrophobic core (that can be loaded with immunostimulants) and a chitosan shell that can associate antigens. For this concept, the authors utilized imiquimod and hepatitis B surface antigens as model molecules. The nanovaccine formulation was successfully internalized by macrophages, inducing the secretion of pro-inflammatory cytokines and eliciting a specific and predominant Th1-mediated immune response. More recently, [PERSON] et al. [138] created delivery vehicles for antigens based on transfer-osomes with opposite surface charges, and transdermal formulations were administered through dissolving micromeedles. In their study, cationic nanocarriers with ovalbumin as the model antigen performed better than anionic vehicles, displaying improved escape capacities from endocytic compartments, accumulating in higher amounts within lymph nodes, activating more efficiently DC maturation, and inducing Th1 immunity. Figure 7: Schematic representation of how nanovaccines activate immune responses. Reprinted from an open-access source [121].