Gold nanoparticles (AuNP) carriers are biocompatible, protect RNA from degradation, and have tunable shape, size, and optical properties. Two approaches for the design of AuNP nucleic acid carriers are covalent attachment and supramolecular assembly. To covalently conjugate RNA with the AuNP core, a thiol group is introduced onto the RNA 344 to create RNA monolayers by linking RNAs directly to the AuNP surface via Au-thiol bonds. The dense shell of oligonucleotides on the surface of the AuNPs inhibits nuclease degradation. Since AuNP-RNA conjugates can be delivered transdermally, they may be useful for gene therapy to treat cutaneous tumors, skin inflammation, and other skin disorders. To electrostatically attract the negatively charged nucleic acids, AuNPs have been functionalized by structurally modifying them adding positively charged molecules such as polymers and amino acids. Spherical nucleic acids are three-dimensional nucleic acid nanostructures that are functionalized, packed densely, and oriented spherically around a nanoparticle core. Since they are resistant to nuclease degradation and are taken up efficiently by cells they show promise as therapeutic agents. 347 Despite their high negative charge (zeta potential less than -30 mV), they rapidly and efficiently enter cells by caveolin-mediated endocytosis and regulate gene expression. Immunomodulatory spherical nucleic acids that stimulate or regulate immunity by engaging toll-like receptors are a promising immunotherapy for cancers including triple-negative breast cancer, prostate cancer, and melanoma. Magnetic nanoparticles deliver nucleic acid by magnetofection, which is the application of a magnetic field. The nanoparticles need functionalization (i.e., surface modifications) to enhance their performance as a magnetic gene delivery vector. The earliest magnetic core-shell nanoparticles for gene delivery were iron oxide nanoparticles stabilized with high molecular weight PEI, with a hydrodynamic diameter of 200 nm and positive zeta potential. Nucleic acids with magnetic nanoparticles increased transfection efficiency by about 1000-fold compared to non-magnetic vectors. A variety of formulations of PEI-coated superparamagnetic iron oxide nanoparticles complexed with nucleic acids have been reported. Other polymers and lipids have also been used to functionalize iron oxide nanoparticles for nucleic acid delivery. These include biodegradable polylactide magnetic nanoparticles containing oleate-coated magnetite and surface modified with PEI-oleate for nucleic acid binding 358 and mesoporous silica nanoparticles decorated with magnetite nanocrystals to yield highly efficient transfection agents. Mesoporous silica nanoparticles (MSN) are hollow particles that can encapsulate a wide range of drugs after surface modification. Silica nanoparticles allow slow release of the cargo as they degrade slowly in the body to nontoxic byproducts. The advantages of MSNs as drug delivery vehicles include a large surface area, tunable pore sizes, simple surface modifications, and efficient encapsulation of cargo molecules. Mesoporous and solid silica nanoparticles are synthesized using the sol-gel method in which a silica precursor is hydrolyzed and then condensed to generate spherical particles. Tetraethyl orthosilicate, the usual silica precursor, provides good control by modification of the synthesis conditions. Silica nanoparticles with a spiky nanotopography can enlarge the surface area for binding RNA molecules. To bind the negatively charged nucleic acids and enhance cellular uptake, silica particles are modified with positively charged compounds such as PLL or PEI, or with branched PEI to enhance the binding of the nucleic acids. . After cell entry by endocytosis, the acidic pH in the endosomes changes the charge of PEI resulting in the dissociation and release of the RNA.