## 2 Design and Engineering of Nanostructured Drug Delivery Systems
Nanoparticles have potential anti-tumor activities and qualities that make them useful as therapeutic agents or vaccine adjuvants. Features like size, surface charge, functionalization, hydrophobicity or hydrophilicity, and the capacity to bind diverse biomolecules all substantially impact nanoparticle biocompatibility with target immune cells. Nanomaterials can be created to imitate specific foreign signals, modify the adaptive immune response, and develop new biological systems for use in immunotherapy. Nonetheless, certain nanoparticle properties have been demonstrated to cause considerable immutotoxicity, such as activating stress-related genes, membrane rupture, and oxidative stress, and producing pro-inflammatory cytokines [3; 30; 31; 32]. As a result, selecting and designing materials with the appropriate qualities for immunotherapy requires a thorough approach. Originally, silica and metal-based nanoparticles were used because of their ability to trigger a desired immunological response, either directly or indirectly, via associated antibodies or medicines. However, metal nanoparticles, such as gold nanoparticles, have been shown to be nondegradable, potentially leading to bioaccumulation, while silica nanoparticles have been observed to require surface functionalization to enhance their biocompatibility, and their effects on immune cells are reliant on their size, structure,  
Figure 3: Stimuli-responsive nanoparticles (srNPs) for controlled delivery in cancer immunotherapy. (**A**) Design of srNPs activated by endo- and/or ex-stimuli, including pH, enzyme presence, high ROS/GSH concentration, photons, US, magnetic field, and radiation, for smart drug release. (**B**) srNPs activated by endo- and/or ex-stimuli with controlled immunomodulator release for primary tumor treatment. Reprinted from an open-access source [29]. and other physical features [3]. Thus, despite the initial popularity of these inorganic nanomaterials, more recent studies have rather focused on developing delivery systems for immunotherapeutic agents based on organic nanoparticles. Polymers represent an appealing class of materials for fabricating nanocarriers with a wide range of polymeric nanoparticles, which are demonstrated to be biocompatible, biodegradable, soluble, stable, and versatile. Used alone, in blends, or combined with other types of materials, polymer-based nanostructures can be used as vehicles for a variety of cargos (e.g., drugs, genes, vaccines, biomolecules, imaging agents, etc. ), improving their therapeutic activity while diminishing off-target toxicity [33; 34]. Moreover, polymeric systems can improve immunotherapeutic approaches due to their adjustable physicochemical properties and the possibility of functionalization with different surface ligands. Polymeric nanoparticles can target dendritic cells (which are crucial for initiating immune responses), making them highly beneficial for immunotherapeutic strategies. Furthermore, studies suggest that improving the size, shape, surface charge, and hydrophobicity of nanoparticles enhances the transport of immunotherapeutic agents to malignancies. This precise control facilitates the combination of immunotherapy treatments, avoids the reoccurrence of tumors, promotes the development of long-lasting immunological memory, and improves patient outcomes by lowering toxicity and adverse events associated with the immune system [34; 35]. Interesting prospects in immunotherapy are also offered by lipid nanoparticles (LNPs). LNPs have been extensively investigated because they can be manufactured on a large scale while maintaining precise manipulation of their morphology and lipid composition [36; 37; 38]. Their application in tumor immunotherapy has greatly enhanced the effectiveness of antitumor treatment while minimizing negative effects on the body as a whole. Particularly, LNPs were remarked to be valuable carriers for delivering mRNA for cancer immunotherapy. LNPs provide protection to the mRNA and further augment its internalization and distribution into cells.