Nanotechnology increasingly plays a significant role in modern medicine development. The clear benefits of using nanomaterials in various biomedical applications are often challenged by concerns about the lack of adequate data regarding their toxicity. Two decades of nanotoxicology research have shown that the interactions between nanoparticles (NPs) and biosystem are remarkably complex. This complexity derives from NPs' ability to bind and interact with biological cells and change their surface characteristics. One area of interest involves the interactions between NPs and the immune component. Immune system's function in the maintenance of tissue homeostasis is to protect the host from unfamiliar agents. This is done through effective surveillance and elimination of foreign substances and abnormal self cells from the body. Research shows that nanomaterials can stimulate and/or suppress the immune responses, and that their compatibility with the immune system is largely determined by their surface properties. NP size, shape, composition, protein binding and administration routes seem to be the main factors that contribute to the interactions of NPs with the immune system. In the present article, we focus on the relationship between effective physiochemical properties of NPs and their immunogenic effects. In addition, we review more details about immunological responses of different types of NPs. Understanding the interactions of nanomaterials with the immune system is essential for the engineering of new NP-based systems for medical applications.

Methotrexate (MTX) is one of the most effective therapeutics to treat different types of solid tumors; however, it suffers low permeability limiting its bioavailability and cellular uptake. To tackle this, we aim to design and fabricate different types of cell-penetrating peptides (CPPs) to improve the intracellular uptake of MTX without causing any immunogenic response. CPPs were synthesized by the solid-phase peptide synthesis method. Peptide-MTX conjugates were prepared via covalent binding of peptide and drug molecule. CPPs and peptide-E₈ nanoparticles were characterized using zeta-sizer and scanning electron microscopy. Cytotoxicity of CPPs and peptide-MTX conjugates was evaluated by MTT assay. An enzyme-linked immunosorbent assay was employed to assess the IL-6 and TNF-α cytokine release profile. Amongst all sequences, W₄R₄-MTX possessed the highest loading efficiency (97%) and drug to peptide percentage (24.02%). The lowest loading efficiency (36%) and drug to peptide percentage (8.76%) were seen for NGRWK-MTX conjugates. The NGRWR peptide and NGRWR-E₈ nanoparticles had acceptable size (~100 nm) with spherical and rod-like structures, respectively. The selected CPPs and peptide-MTX conjugates did not show any cytotoxicity or immunogenicity. The fabricated peptides are represented as promising carriers to improve the intracellular delivery of MTX to cancer cells with low immunogenic and cytotoxic effects on normal cells.