The Size-dependent Cytotoxicity of Amorphous Silica Nanoparticles: A Systematic Review of in vitro Studies

Figures & data

Figure 1 Flow chart of systematic selection of articles.

Table 1 Quality Assessment of Included Studies

Source	Scientific Background Described	Study Purpose Described	Study Model Justified	Study Design Described	Endpoint Specific Defined	Cell Culture Described	Statistical Method Corrects	Endpoint Measurement Described	Concentration Response Described	Result Interpreted and Discussed	Study Founded Described	Score	Study Quality
Wottrich^Citation25 (2004)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Lin^Citation71 (2006)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Yu^Citation59 (2009)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Thomassen^Citation37 (2010)	√	√	✘	√	√	√	√	√	√	√	√	10	Good
Park^Citation84 (2009)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Waters^Citation46 (2009)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Napierska^Citation2 (2009)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Wang^Citation61 (2009)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Morishige^Citation79 (2010)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Ye^Citation39 (2010)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Park^Citation85 (2010)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Kim^Citation86 (2010)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Yuan^Citation64 (2010)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Akhtar^Citation72 (2010)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Yang^Citation54 (2010)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Ye^Citation40 (2010)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Gonzalez^Citation20 (2010)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Nabeshi^Citation56 (2011)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Nabeshi^Citation47 (2011)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Ariano^Citation65 (2011)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Bauer^Citation75 (2011)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Lu^Citation77 (2011)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Li^Citation42 (2011)	√	√	✘	√	√	√	√	√	√	√	√	10	Good
Corbalan^Citation35 (2011)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Wang^Citation63 (2011)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Al-Rawi^Citation69 (2011)	√	√	√	√	√	√	√	√	✘	√	√	10	Good
Uboldi^Citation82 (2012)	√	√	✘	√	√	√	√	√	√	√	√	10	Good
Gong^Citation55 (2012)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Napierska^Citation26 (2012)	√	√	√	√	√	√	√	√	✘	√	√	10	Good
Passagne^Citation68 (2012)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Kim^Citation48 (2012)	√	√	√	√	√	√	√	√	√	√	√	11	Good
McCarthy^Citation32 (2012)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Xu^Citation33 (2012)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Gualtieri^Citation74 (2012)	√	√	✘	√	√	√	√	√	√	√	√	10	Good
Panas^Citation27 (2012)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Gazzano^Citation80 (2012)	√	√	✘	√	√	√	√	√	√	√	√	10	Good
Stępnik^Citation81 (2012)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Napierska^Citation38 (2012)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Gehrke^Citation44 (2013)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Kasper^Citation31 (2013)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Freese^Citation17 (2014)	√	√	√	√	√	√	√	√	✘	√	√	10	Good
Kim^Citation66 (2014)	√	√	✘	√	√	√	√	√	√	√	√	10	Good
Kusaka^Citation50 (2014)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Vo^Citation70 (2014)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Horie^Citation73 (2014)	√	√	✘	√	√	√	√	√	√	√	√	10	Good
Mendoza^Citation51 (2014)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Docter^Citation78 (2014)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Nemmar^Citation36 (2014)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Kojima^Citation53 (2014)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Xue^Citation41 (2014)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Fede^Citation21 (2014)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Gonzalez^Citation22 (2014)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Nagakura^Citation57 (2014)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Tarantini^Citation43 (2015)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Kim^Citation83 (2015)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Tokgun^Citation23 (2015)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Guichard^Citation34 (2016)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Li^Citation28 (2016)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Saikia^Citation12 (2016)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Manganelli^Citation62 (2016)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Nakanishi^Citation52 (2016)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Gong^Citation58 (2017)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Nishijima^Citation18 (2017)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Vicente^Citation60 (2017)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Premshekharan^Citation49 (2017)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Liu^Citation24 (2017)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Låg^Citation30 (2018)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Wang^Citation15 (2018)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Fritsch-Decker^Citation45 (2019)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Kim^Citation13 (2019)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Lee^Citation16 (2019)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Kamikubo^Citation3 (2019)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Du^Citation67 (2019)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Li^Citation29 (2019)	√	√	√	√	√	√	√	√	✘	√	√	10	Good
Leibe^Citation10 (2019)	√	√	√	√	√	√	√	√	√	√	√	11	Good
Wang^Citation76 (2020)	√	√	√	√	√	√	√	√	√	√	√	11	Good

Notes: √=Yes; ✘=No.

Table 2 In vitro Studies on Cytotoxicity of Amorphous Silica Nanoparticles (aSiNPs) with Different Sizes

Source	Cell Type	Particle Primary Size	Aggregates/Agglomerates	Exposure Dose	Exposure Time	Assay(s)/Method(s)	Size-dependent Cytotoxicity
Wottrich^Citation25 (2004)	A549 THP-1 Mono Mac 6	S-60, 100 nm	–	10–200 μg/mL	24 h	LDH activity assay	Cytotoxicity: 60 nm >100 nm
Lin^Citation71 (2006)	A549	15, 46 nm	√	10–100 μg/mL	24, 48, 72 h	LDH activity assay and Sulforhod amine B assay(SRB)	Not significant
Yu^Citation59 (2009)	HEL-30 cells	S-30, 48, 118, 535 nm	–	0–200 μg/mL	24 h	MTT assay and LDH activity assay	Cytotoxicity: 30 nm >48 nm >118 nm >535 nm
Thomassen^Citation37 (2010)	EAHY926 J774	Lu-11, 14, 15 nm Ly-2, 26, 34, 36 nm S-18, 60, 104, 335 nm	No substantial aggregation,  except for the Ludox-Sil-15, Stober-Sil-104, Sober-Sil-18, and Lys-Sil-2 particles	0–2000 μg/mL	24 h	MTT assay and WST-1 assay	The smaller the particle size, the greater the cytotoxicity.
Park^Citation84 (2009)	D3	S-10, 30, 80, 400 nm	No substantial aggregation, except for the 10 nm particles	0.3–100 μg/mL	24 h, 10 days	WST-1 assay	Not significant; cytotoxicity: 30 nm >10 nm>80 nm and 400 nm
Waters^Citation46 (2009)	RAW 264.7	P-10, 50, 150, 300, 500 nm Lu-7, 16 nm	Moderate degree of aggregation of 10-nm particles	0–1000 μg/mL	24 h	MTT assay	The smaller the particle size, the greater the cytotoxicity.
Napierska^Citation2 (2009)	EAHY926	L-14,15 nm S-16, 19, 60, 104, 335 nm	–	100 μg/mL	24 h	MTT assay and LDH activity assay	The smaller the particle size, the greater the cytotoxicity.
Wang^Citation61 (2009)	HEK293	20, 50 nm	–	0–1000 μg/mL	24 h	MTT assay	Cytotoxicity: 20 nm >50 nm
Morishige^Citation79 (2010)	TPH-1	30, 50, 60, 300, 1000 nm	–	100 μg/mL	24 h	Standard methylene blue assay	Cytotoxicity: 300, 1000 nm >30, 50, 70 nm
Ye^Citation39 (2010)	H9c2(2–1)	S-21, 48 nm	–	0.1–1.6 mg/mL	12, 24, 36.48 h	LDH activity assay and MTT assay	Cytotoxicity: 21 nm >48 nm
Park^Citation85 (2010)	HaCaT	7 nm 10–20 nm	√	0–300 μg/mL	48 h	MTT assay	Not significant
Kim^Citation86 (2010)	SH-SY5Y	Lu-15.3, 16.9 nm	–	10, 100, 1000 ppm	48 h	MTT assay	Not significant
Yuan^Citation64 (2010)	PC12 HEK293	S-20, 50, 80,140, 280, 760 nm	–	20–2000 μg/mL	24 h	MTT assay	Cytotoxicity: 20 nm >50 nm >80 nm >140, 280, 760 nm
Akhtar^Citation72 (2010)	A549	S-10, 80 nm	√	50–400 μg/mL	48 h	MTT assay and LDH activity assay	Not significant
Yang^Citation54 (2010)	HaCaT	15, 30, 365 nm	–	2.5–80 μg/mL	24 h	CCK-8 assay and FITC apoptosis detection	Cytotoxicity: 15 nm>30 nm>365 nm
Ye^Citation40 (2010)	L-02	21, 48, 86 nm	–	200–1000 μg/mL	12, 24, 36, 48 h	MTT assay and LDH activity assay and V-FITC/PI apoptosis assay	Cytotoxicity: 21 nm >48 nm >86 nm
Gonzalez^Citation20 (2010)	A549	S-16, 60, 104 nm	–	10–500 mg/mL	24 h	MTT assay	Cytotoxicity: 16 nm >60 nm >104 nm
Nabeshi^Citation56 (2011)	HaCaT	70, 300, 1000 nm	–	10–1250 μg/mL	24 h	LDH activity assay	Cytotoxicity: 70 nm >300, 1000 nm
Nabeshi^Citation47 (2011)	RAW264.7	70, 300, 1000 nm	–	10, 30 μg/mL	5 days	WST-8 assay	Cytotoxicity: 70 nm > 300, 1000 nm
Ariano^Citation65 (2011)	GT1-7	S-50, 200 nm	–	15–292 μg/mL	24, 72 h	Count the cell number	Cytotoxicity: 50 nm >200 nm
Bauer^Citation75 (2011)	HUVECs	S-16, 41, 80, 212, 304 nm	–	1000, 15,000, 30,000 NP/cell	24, 48 h	MTT assay and LDH activity assay	Cytotoxicity: 304 nm >212 nm >16, 41, 80 nm
Lu^Citation77 (2011)	HepG2 L-02	7, 20, 50 nm	–	20–640 μg/mL	48 h	MTT assay	Not significant; cytotoxicity: 20 nm >7 nm >50 nm
Li^Citation42 (2011)	HepG2	19, 43, 68, 498 nm	Moderate degree of aggregation of 19 nm particles	12.5–200 μg/mL	24 h	CCK-8 assay and LDH activity assay and annexin V-FITC/PI apoptosis assay	Cytotoxicity: 19 nm >43 nm>68 nm >498 nm
Corbalan^Citation35 (2011)	HUVECs	10, 50, 150, 500 nm	–	1–100 μg/mL	3, 7, 15, 30 h	LDH activity assay	Cytotoxicity: 10 nm >50 nm >150, 500 nm
Wang^Citation63 (2011)	PC12	20, 50 nm	–	0–300 μg/mL	12, 24, 36, 48 h	MTT assay	Cytotoxicity: 20 nm >50 nm
Al-Rawi^Citation69 (2011)	HeLa	70, 200, 500 nm	—	50 μg/mL	24 h	LDH activity assay and WST-1 assay	Cytotoxicity: 70 nm >200 nm, 500 nm
Uboldi^Citation82 (2012)	Balb/3T3	10–25, 5-30 nm 15, 35, 80, 90 nm	No substantial aggregation, except for the 10–25 nm and 5–30 nm particles	1, 10, 100 μg/mL	72 h	MTT assay	Not significant; Only 80 nm silica nanoparticles produced significant cytotoxicity.
Gong^Citation55 (2012)	HaCaT	15, 30, 100 nm	–	0–100 μg/mL	24 h	CCK-8 assay	Cytotoxicity: 15 nm >30 nm >100 nm
Napierska^Citation26 (2012)	A549 THP-1	S-2, 16, 60, 104 nm	–	5 μg/cm^2	24 h	LDH activity assay and MTT assay	Cytotoxicity: 2 nm >16 nm >60 nm >104 nm
Passagne^Citation68 (2012)	HK-2 LLC-PK1	20, 100 nm	–	5–500 μg/mL	24, 48, 72 h	WST-1	Cytotoxicity: 20 nm >100 nm
Kim^Citation48 (2012)	U937	15, 50, 100 nm	–	0–2000 μg/mL	24 h	CCK-8 assay	Cytotoxicity: 15 nm >50 nm >100 nm
McCarthy^Citation32 (2012)	Calu-3	10, 150, 500 nm	–	0–100 μg/mL	2, 6, 18, 24 h	MTT assay	Cytotoxicity: 10 nm >150,500 nm
Xu^Citation33 (2012)	HFL‐I	20, 80 nm	–	250–2000 μg/mL	48 h	MTT assay	Cytotoxicity: 20 nm >80 nm
Gualtieri^Citation74 (2012)	BEAS-2B	30, 50 nm	√	100 μg/mL	20 h	LDH activity assay	Not significant
Panas^Citation27 (2012)	RAW264.7 A549	12, 25 nm	√	10–200 μg/mL	24 h	LDH activity assay and Alamar Blue assay	Cytotoxicity: 12 nm >25 nm
Gazzano^Citation80 (2012)	MH-S	Pyr-7, 40 nm S-1000 nm	√	0–160 μg/cm^2	24 h	LDH activity assay	Not significant; cytotoxicity: 7, 40 nm >1000 nm
Stępnik^Citation81 (2012)	3T3-L1 WI-38	Lu-21, 30 nm	Partial aggregation	40–800 μg/mL	72 h	LDH activity assay and WST-1 assay	Cytotoxicity: 30 nm >21 nm
Napierska^Citation38 (2012)	EA.hy926	S-16, 60 nm	–	25–50 μg/mL	1, 2.5, 4, 24 h	MTT assay and LDH activity assay	Cytotoxicity: 16 nm >60 nm
Gehrke^Citation44 (2013)	HT29	12, 40, 200 nm	No substantial aggregation, except for the 12 nm particles	0.1–500 μg/mL	24, 48, 72 h	SRB assay and WST-1 assay and LDH activity assay	Cytotoxicity: 12 nm >40 nm >200 nm
Kasper^Citation31 (2013)	H441 ISO-HAS-1	30, 70, 300 nm	Partly agglomerated of 30 nm particles	6–600 μg/mL	4 h	MTS assay and LDH activity assay	Cytotoxicity: 30 nm >70 nm >300 nm
Freese^Citation17 (2014)	HUVEC	30, 70 nm	The 30 nm particles tended to agglomerate with time	60–150 μg/mL	24 h	MTS assay and LDH activity assay	Cytotoxicity: 70 nm >30 nm
Kim^Citation66 (2014)	U373MG	20, 100 nm	–	0–30 mg/mL	24 h	CellTiter-Glo luminescent assay	Cytotoxicity: 20 nm >100 nm
Kusaka^Citation50 (2014)	BMDMs	30, 100, 300, 1000, 3000, 10,000 nm	–	0.03–0.3 mg/mL	2 h	LDH activity assay	Cytotoxicity 30, 100, 300 nm> 1000 nm >3000,10,000 nm
Vo^Citation70 (2014)	RTgill-W1 RTgut-GC RTL-W1 RTBrain FHML2-6 FHMT-W1GFB3C GFSk-S1 GloFish ZEB2J EelBrain HEW	S-16, 24, 44 nm	–	1.8–1800 μg/mL	24 h	Alamar Blue assays	Cytotoxicity: 16 nm >24 nm >44 nm
Horie^Citation73 (2014)	A549 HaCaT	S-7, 25, 34 nm	√	10–1000 μg/mL	24, 48 h	LDH activity assay and MTT assay	Not significant
Mendoza^Citation51 (2014)	PBMC cells	S-10, 100 nm	10 nm particles in culture medium tend to aggregate	50–4000 ppm	24, 48 h	PI staining with flow cytometer	Cytotoxicity: 10 nm >100 nm
Docter^Citation78 (2014)	Caco-2	20, 30, 100 nm	√	6–600 μg/mL	4, 24 h	MTT assay	Not significant; 30 nm silica particles produced significant cytotoxicity
Nemmar^Citation36 (2014)	HUVEC	50, 500 nm	–	0.1–100 μg/mL	24 h	CellTiter-Glo^® Luminescent Cell Viability Assay	Cytotoxicity: 50 nm >500 nm
Kojima^Citation53 (2014)	KUP5	30, 70, 300 nm	The particles of SNP70 and SNP300 appeared to be loosely aggregated in DMEM cell culture medium	1–30 μg/cm^2	24 h	WST-1 assay	Cytotoxicity: 30 nm >70 nm >300 nm
Xue^Citation41 (2014)	BRL	20 nm, 0.5–6 μm	20 nm silica nanoparticle aggregates were visible	0.005−1 mg/mL	18, 24 h	Thiazolyl blue tetrazolium bromide assay and LDH activity assay and MTT assay	Cytotoxicity: 20 nm >0.5–6 μm
Fede^Citation21 (2014)	A549	Lu-9, 18 nm	–	0.01–0.05 mg/mL	2 h	MTS-assay	Cytotoxicity: 9 nm >18 nm
Gonzalez^Citation22 (2014)	A549	Lys-12, 40 nm, S-28, 59, 139, 174 nm	–	0–1056 μg/mL	40 h	Peak flow green flow cytometry-based cytotoxicity measurement	Cytotoxicity (absence of serum): L-12 nm >L-40 nm; S-28 nm >S-59 nm >S-139 nm >S-174 nm
Nagakura^Citation57 (2014)	HaCaT	30, 70, 300 nm	30 nm particles approximately uniformly dispersed in the medium	0–50 μg/cm^2	24 h	WST-1 assay	Cytotoxicity: 30 nm >70 nm >300 nm
Tarantini^Citation43 (2015)	Caco-2	15, 55 nm	15 nm particles formed aggregates	0–256 μg/mL	24 h	XTT assay	Cytotoxicity: 15 nm >50 nm
Kim^Citation83 (2015)	A549 HepG2 NIH/3T3	S-20, 40, 60, 80, 100, 150, 200 nm	√	10–500 μg/mL	24, 72 h	LDH activity assay and MTT assay	Not significant
Tokgun^Citation23 (2015)	A549	S-6, 15, 30, 55 nm	–	0.1–1000 μg/mL	72 h	CytoToxGlo kit and TUNEL analysis	Cytotoxicity: 6 nm >15 nm >30, 55 nm
Guichard^Citation34 (2016)	V79	Pyr 20: 19±5 nm	√	1.25–100 μg/cm^2	24 h	WST-1	Cytotoxicity: Col15 >Pyr 20=Pre 20 >Pyr 25/70=Col 40/80.
		Pyr 25/70: 71±25/25±8 nm
		Pre 20: 19±3 nm
		Col 15: 15±4 nm
		Col 40/80: 79±3/38±5 nm
Li^Citation28 (2016)	BEAS-2B	S-40, 60, 200 nm	–	6.25–100 μg/mL	6, 12, 24 h	MTT assay and LDH activity assay	Cytotoxicity: 40 nm >60 nm >200 nm
Saikia^Citation12 (2016)	RAW 264.7	S-50, 500 nm	–	4–500 μg/mL	24 h	CCK-8 assay and LDH activity assay	Cytotoxicity: 50 nm >500 nm
Manganelli^Citation62 (2016)	HEK293	20, 50 nm	–	25–200 μg/mL	12, 24, 36, 48 h	MTT assay	Cytotoxicity: 20 nm >50 nm
Nakanishi^Citation52 (2016)	mBMDCs	30, 70, 300 nm	–	1–20 μg/cm^2	24 h	LDH activity assay	Cytotoxicity: 30 nm >70 nm >300 nm
Gong^Citation58 (2017)	HaCaT HaCaT-shPARP-1	15 nm,1–5 μm	–	0–200 μg/mL	24 h	CCK-8 assay and LDH activity assay and MTT assay and flow cytometric analysis	Cytotoxicity: 15 nm>1–5 μm
Nishijima^Citation18 (2017)	TPH-1	10, 30, 50, 70, 100, 300, 1000 nm	–	12.5–200 μg/mL	6, 12, 24 h	LDH activity assay	Not significant
Vicente^Citation60 (2017)	K17 HDF	Lu-20 nm 70, 200, 500 nm	70 nm silica nanoparticle aggregates were visible	5–200 μg/mL	24 h	LDH activity assay and WST-1 assay and PI staining and nuclei counting	Cytotoxicity: 20 nm >70 nm ≥200, 500 nm
Premshekharan^Citation49 (2017)	THP-1	50 nm, 2 μm	The particles of 2 μm appeared to be loosely aggregated in cell culture medium	1–100 μg/mL	22 h	MTT assay	Cytotoxicity: 50 nm >2 μm
Liu^Citation24 (2017)	A549 A549-shNrf2 A549-shRNA	10–20 nm, 1–5 μm	–	0–100 μg/mL	24 h	CCK-8 assay and annexin V FITC apoptosis detection kit	Cytotoxicity: 10–20 nm >1–5 μm
Låg^Citation30 (2018)	BEAS-2B HBEC3-KT	10, 50 nm	10 nm particles showed polydispersity in media	0–200 μg/mL	20 h	LDH activity assay	Cytotoxicity: 10 nm >50 nm
Wang^Citation15 (2018)	HUVECs	S-10, 25, 50, 100 nm	A degree of aggregation of four particles	1–25 μg/mL	24 h	CCK-8 assay and flow cytometry assay	Cytotoxicity: 10 nm >25 nm >50 nm >100 nm
Fritsch-Decker^Citation45 (2019)	HCT116	12, 70, 200, 500 nm	12 nm NPs were already aggregated to 232 nm in medium without FBS	0–100 μg/mL	24, 48 h	LDH activity assay and Alamar Blue assay	Cytotoxicity: 12 nm >70 nm>200, 500 nm
Kim^Citation13 (2019)	HepG2 A549 SW480	S-20, 30, 40, 50 nm	Particles aggregates formed in PBS solution containing FBS	5–500 μg/mL	24 h	WST-1 assay	Cytotoxicity: 20, 30 nm >40, 50 nm
Lee^Citation16 (2019)	HUVECs	S-20, 30, 40, 50 nm	–	5–25 μg/mL	24 h	FITC-annexin-V & propidium iodide (PI) assay	Cytotoxicity: 20 nm >30, 40, 50 nm
Kamikubo^Citation3 (2019)	Rat hippocampal cells HEK293.	10, 30, 100, 400, 1500 nm	–	0.0001−5 mg/mL	2 h	CTG assay and MTT assay and propidium iodide (PI) assay	Cytotoxicity: 10 nm >30 nm>100 nm>400 nm >1500 nm
Du^Citation67 (2019)	N9 bEnd.3 HT22	S-50, 100, 300 nm	–	25–200 μg/mL	24 h	MTS assay	Cytotoxicity in N9 cells: 50 nm >100 nm >300 nm
Li^Citation29 (2019)	BEAS-2B	S-40, 60, 200 nm	–	25 μg/mL	24 h	CCK-8 assay	Cytotoxicity: 40 nm>60 nm>200 nm
Leibe^Citation10 (2019)	RAW 264.7 A549	12, 50 nm	Large numbers of 50 nm particles agglomerates in the absence of serum	10–100 μg/mL	24 h	LDH activity assay and Alamar Blue assay	Cytotoxicity: 12 nm >50 nm
Wang^Citation76 (2020)	HUVECs	20, 100 nm	–	0–200 μg/mL	24 h	CCK-8 assay and LDH activity assays	Cytotoxicity: 100 nm >20 nm

Figure 2 Fan-shaped diagram of the relationship between cytotoxicity of aSiNPs and its particle size.

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