Table 3.

Common chemical methods used for surface modification of CaP-based nanoparticles with different types of macromolecules such as nucleic acids (e.g., siRNA and DNA), cancer targeting agents (e.g., peptides and antibodies), and polymers (e.g., PEG, PEI and hyaluronic acid), designed for in vivo cancer therapy studies. (PEI:Polyethylenimine)

Method Description	Common Macromolecules	Advantages	Disadvantages	Examples
Macromolecules used to form micelles for CaP mineralization	Liposomes, hyaluronic acid and peptides conjugated to polymers (e.g., PEG)	- Tunable CaP shell thickness - Protection of CaP-coated macromolecules	- Safety of the synthetic macromolecules for clinical translation - Often requires additional surface modification	[60, 68, 74, 77]
Macromolecules used as homogenously dispersed templates for controlled growth of mineralized CaP’s (no micelles)	Nucleic acids and proteins (e.g., BSA)	- Mostly spherical - Room temperature synthesis which maintains bioactivity	- Aggregation of NPs - Limited size and shape tenability - Often requires additional surface modification	[67, 70]
Surface modification of mineralized CaP’s by electrostatic adsorption of macromolecules	Cancer targeting molecules and nucleic acids	- Easy procedures -Applicable for a large number of macromolecules	- Detachment of the physically adsorbed macromolecules due to their weak bonds	[61, 62]
Covalent bonding of macromolecules to the surface of mineralized CaP’s	Cancer targeting molecules, Polymers (e.g., PEG or PEI derivatives) and hyaluronic acid	- Long-term stability in biological environment - Longer blood circulation time - Lower cost of the macromolecules	- Multiple steps and sensitive conjugation steps	[23, 55, 65]