Table 1.

A brief summary of fabricating CMNDDs in vitro

Types of interaction	Approaches	Pros.	Cons.
Ligand-receptor interaction	Natural cell surface protein marker-mediated interaction [25–45]	Natural cell surface protein markers (such as CD) are widely expressed, and the fabrication is relatively easy.	The interaction is not specific enough, since some CD, such as CD45, CD3 are expressed on different cells, and the interaction could be influenced by the different conditions in vivo.
	Gene-engineered cell marker-mediated interactions [46]	The interaction is specific with high efficacy.	Gene-engineering is required for the design.
Other non-covalent interaction	Hydrophobic interaction [47]	NPs are anchored to the cell membrane by hydrophobic moieties.	The interaction may affect cell membrane integrity and cell function.
	Electrostatic interaction [31, 33, 48, 49]	Positively charged NPs attach to negatively changed cell membrane.	The interaction could be influenced by surrounding environments and the stability of the CMNDDs is concerning.
	Host-guest interaction [50]	This approach can be widely applied in fabricating CMNDDs regardless the types of cell carriers and NPs. The interaction is specific.	Chemical modification is needed on both cell carriers and NPs.
	Mechanical, osmotic and oxidative stress [51]	This approach can be generally used in fabricating CMNDDs.	The method could be harmful to cell membrane and cell function.
Covalent interaction	SH-Mal [52]	This approach is under the mild reaction conditions with high efficacy.	This approach is limited by the SH amount on cell surface and could affect cell function.
	Azido-DBCO [53]	This approach is under the mild reaction conditions with high efficacy.	This approach relies on the incorporation efficiency of azido sugars and is time-consuming.
	TEOS- APTES [54]	This approach provides silica layer to cells.	The silicification could influence the cell proliferation and cell viability.
	EDC-Sulfo/NHS [55]	This approach is under the mild reaction conditions with high efficacy.	This approach is limited by the amino amount on cell surface and could affect cell function.
	Schiff base [56]	This approach can be applied in various cell types.	Oxidation reaction is processed on the cell surface, which could influence the cell function.
	SPAAC [57]	This approach is under the mild reaction conditions with high efficacy	Chemical modification is needed on both cell carriers and NPs.
Internalization	The internalization of NPs by cell carries are mediated by endocytosis, pinocytosis, and phagocytosis [58–60].	This approach is not limited by either the cell types or the NPs; in addition, this approach is easy in practice.	The internalized NPs could be exocytosed by cell carriers, thus affecting the stability of CMNDDs. Additionally, the internalized NPs could regulate the cell behaviors, such as activation and differentiation. The NPs could inhibit the cell viability.

Note CD: cluster of differentiation, SH: thiol, Mal: maleimide, DBCO: dibenzocyclooctyne, TEOS: tetraethyl orthosilicate, APTES: 3-Aminopropyl) triethoxysilane, EDC: N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride, Sulfo-NHS: N-hydroxysulfosuccinimide sodium salt. SPAAC: strain-promoted azide-alkyne cycloaddition reaction