## 2 Functionalization of CDs
### Secondary Functionalization or Surface Modification
The ring-opening polymerization is employed in which a cyclic monomer opens up to form a polymer chain that is covalently bonded to the CD surface (Figure 4e). This technique can improve the water dispersibility and biocompatibility of CDs. For example, [PERSON] et al. prepared CDs with hydroxyl groups using \(\alpha\)-cyclodextrinrin as the carbon precursor in a hydrothermal treatment and achieved the surface modification of CDs using the anionic ring-opening glycidol polymerization [96]. The copolymerization process resulted in the formation of hyperbranched polyglycerol (HPG) on the surface of CDs. The resulting CDs-g-HPG exhibited strong green fluorescence, low cytotoxicity, and improved hemocompatibility, enhancing their potential as an effective probe for bioimaging. The surface modification of CDs via Schiff-base reaction involves a primary amine of CDs reacting with carbonyl compounds (aldehyde or ketone), which results in the formation of an imine bond (Figure 4f). Although Schiff bases are stable in alkaline environments, they can undergo hydrolysis into their corresponding amine and carbonyl compounds under acidic conditions, making them suitable candidates for pH-responsive drug delivery systems. Schiff base interactions allow for the attachment of drugs and targeting ligands [97; 98]. For example, [PERSON] et al. synthesized CDs with amine groups using a hydrothermal treatment of \(\alpha\)-phenylenediamine (oPD) as the carbon precursor [99]. The amine groups of CDs reacted with the aldehyde groups of chlorosalicylaldehyde (CS) to result in the formation of CS-CDs. The surface modification of CDs via a \(\pi\)-interaction involves the formation of noncovalent bonds between the graphene-like carbon core of CDs and aromatic molecules (Figure 4g). This method provides a noncovalent method for loading hydrophobic drugs onto CDs, improving their delivery, efficacy, and ability to overcome major challenges in chemotherapy, such as drug resistance, short circulation, and short retention in cells [100]. For example, [PERSON] et al. synthesized APTES-conjugated CDs (Si-CDs) using glycerol and APTES as precursors in a microwave-assisted irradiation [101]. The Si-CDs were further functionalized with dopamine (DA) through the noncovalent \(\pi\)-interaction, resulting in Si-CDs@DA. The surface modification of CDs via metal ion complexation involves the interaction of metal ions with the amine, hydroxyl, or carboxyl groups of both CDs and chelating molecules through coordination bonds (Figure 4h). This modification can drastically influence the optical and magnetic properties of CDs, making them suitable for multimodal imaging such as fluorescence and magnetic resonance imaging (MRI). This metal-CD complex can also be used as a drug carrier and increase the solubility of the drugs. For example, [PERSON] et al. prepared CDs with amine and carboxyl groups using citric acid and triethylenetetramine as the carbon precursors in a hydrothermal method [102]. Tb\({}^{3+}\) ions were coordinated with the carboxyl and amine groups of CDs to form CDs-Tb\({}^{3+}\) complexes, and subsequently, further interacted with guanosine 3\({}^{\prime}\)-diphosphate-5\({}^{\prime}\)-diphosphate (ppGpp) to form Cd-Tb\({}^{3+}\)-ppGpp complexes. The surface modification of CDs via electrostatic interaction involves the noncovalent bond formation between the charged CD surfaces and oppositely charged molecules. Here, oppositely charged species are produced owing to proton transfer (i.e., acid-base reaction) between CDs and molecules (Figure 4i). This method is particularly advantageous in applications to gene delivery, where positively charged CDs can form stable complexes with negatively charged DNA or RNA. Similarly, this method can allow for the adsorption of positively charged drugs such as DOX or dopamine onto negatively charged CDs [38]. For example, [PERSON] et al. synthesized CDs with hydroxyl and carboxyl groups using natural carrot as the carbon source in a hydrothermal method [103].