## 2 Design and Engineering of Nanostructured Drug Delivery Systems  
Numerous nanomaterials have been developed in recent years, significantly advancing the field of nanotechnology and broadening its application across a wide range of disciplines. In particular, nanostructured systems have been recognized as valuable tools in biomedicine, gathering increasing interest for therapeutic applications [2; 17; 18; 19]. Biomedical nanotechnology, involving the design and engineering of sophisticated biomaterials and drug delivery systems, is particularly well-suited for the controlled targeting of the immune system [8; 20]. Related to therapeutic transport, nanostructured systems offer improved delivery of otherwise insoluble drugs, maximizing their bioavailability and reducing the required dosage. Specifically, the amount of carried drug can be reduced by 100-1000 times when delivered by targeted systems to the desired site/cells. In more detail, lower amounts of active pharmaceutical ingredients can be administered as they are only released where needed, and there are no drug losses toward undesired tissues. Thus, nanocarir approaches have the benefit of increasing local drug concentrations while minimizing side effects [21; 22; 23; 24]. Besides of their tailored dimensions and morphologies, customized nanoparticles also exhibit enhanced permeability and retention effects, high thermal conductance, and great electromagnetic radiation absorbance [25]. Moreover, nanoparticles can combine different therapeutic strategies to create multifunctional treatment tools or encompass both therapeutic and diagnostic functions to generate theranostics [9; 21; 26]. Nanomaterials have extremely small sizes, with at least one dimension between 1 and 100 nm. Their sizes are comparable with some bacteria and viruses, which render them capable of interacting with the immune system in manners mimicking natural pathogens [8; 27]. Their size is also advantageous for passing through normally intact physiologic barriers and reaching specific targets for releasing carried agents. Hence, nanoparticles interact at a molecular level with immune cells, leading to immunostimulatory or immunosuppressive responses, thus modulating the immune system and enabling their use for therapeutic purposes [8; 18; 27]. Reciprocally, immune cells also exert certain actions onto nanoparticles, determining aspects like persistence, degradation, or clearance [8]. With these advantageous properties in mind, nanomaterials have started to be explored for use in immune-based therapies targeting a plethora of diseases. Nanosystems interact with the immune system in complex ways, influencing various immune cells, such as antigen-presenting cells (APCs), B cells, and T cells, and can induce both humoral and cell-mediated immune responses. These interactions can be finely tuned by engineering the NPs with specific physicochemical properties--such as size, shape, surface area, and charge--to enhance their recognition and uptake by immune cells, and effectively modulate the immune response [3; 16]. When introduced into living systems, nanoparticles (NPs) are recognized as foreign materials and can either stimulate or suppress the immune system, depending on their chemical nature. This dual capability of NPs to modulate the immune response is crucial for their application in clinical treatments, allowing for the precise control of immune activity in disease prevention and therapy [2; 8]. The combination of intrinsic immunomodulatory properties of nanoparticles and their versatility as nanocarriers can lead to outstanding outcomes when utilizing nanostructuredsystems for delivering immunotherapeutic agents. Various nanoparticles can be employed for transporting immunomodulatory drugs to specific immune cell compartments, potentially mimicking natural immune functions or activating drug release through various triggers (e.g., chemical reactions, targeting ligands, thermodynamic changes, magnetic field, irradiation at specific wavelengths, etc.) [8; 28; 29] (Figure 3).