Table 2.

The preclinical trials of engineered exosomes

Tumor models	Putative name	Clinical therapy	Mechanisms	Ref.
NSCLC	AA-PEG-exoPTX	CT	Target the sigma receptor on lung cancer cells	111
NSCLC	EXO-DTX	CT	Enhance the cytotoxicity of DTX	110
BC	SBC-EV(ICG/PTX)	CT	Improve the cellular uptake of ICG Release the PTX in response to acidic pH in the endo/lysosomes	75
BC	TEX-Liposome-PTX-GNR-PEG	CT	Activate GNR-mediated thermal ablation Increase the level of CD8+ T cells in lungs Improve the concentration of serum cytokines (tumor necrosis factor-α, interlekin-6, and interferon-γ)	87
BC	DOX -TEVGIONs	CT	Block the function of endogenous oncogenic miR-21 Attenuate DOX resistance Enhance T2 contrast in in vitro MR imaging	95
CRC	THLGEXO/5-FU/miR-21i	CT	Induce cell cycle arrest, reduced tumor proliferation, increased apoptosis and rescued PTEN and hMSH2 expressions Reverse drug resistance and significantly enhanced the cytotoxicity in 5-FU-resistant colon cancer	233
CRC	PGM5‐AS1-oxaliplatin-EXO	CT	Prevent proliferation, migration, and acquired oxaliplatin tolerance Reverse drug resistance Activate alternate splicing to downregulate PAEP expression Act as a sponge to upregulate the NME1 expression	89
LC	DDRi@CAT-PD-M1Exos	RT	Relieve tumor hypoxia Enhance DNA damage Inhibit DNA damage repair Polarize M2 macrophages into M1 phenotypes Relieve the immunosuppression of T cells	125
HCC	NIS-EV	RT	Facilitate radioiodine uptake Enhance the antitumor effects of 131I radiotherapy	130
GBM	RGD-siPD-L1-EV	RT	Enhance the targeting efficiency of RGD-EV Reverse radiation-stimulated PD-L1 expression Recruit tumor-associated myeloid cells Increase CD8+ cytotoxic T cells	124
Melanoma/CRC	PASEV	PDT	Release ROS-responsive siPAK4 Prime the TME Boost intratumoral infiltration and immune activation	141
HCC	Er/RB@ExosCD47	PDT	Make the exosomes effectively escape the phagocytosis of MPS Induce ferroptosis after irradiation of 532 nm laser	132
CRC/BC	ChiP-Exo	PDT	Disrupt the membrane integrity Improve the cytosolic delivery of ChiP-Exo under the first-stage light Enhance its nuclear delivery under the second-stage light Activate ROS in situ to disrupt nuclei	142
Pancreatic cancer	Ce6-R-Exo	PDT	Generate ROS inside tumor cells under laser irradiation Increase the release of cytokines from immune cells	187
CRC	I/R@hGLV	PTT	Increase the long blood circulation Improve the macrophages-mediated the phagocytosis of tumor cells Lead to immunogenic cell death Generate TAA Promote the maturation of immature DCs	67
BC	TEX-Liposome-PTX	PTT	Activate the adaptive antitumor immune response Increase the level of CD8+ T cells Improve the concentration of serum cytokines Enhance The therapeutic efficacy combined with thermal ablation, adaptive antitumor immunotherapy, and targeted PTX chemotherapy.	87
BC/ LC	V2C-TAT@Ex-RGD	PTT	Target the cells Enter the nucleus to realize low-temperature PTT	96
BC/ CC	CDs:Gd,Dy-TAT@Exo-RGD	PTT	Accumulate at cancer site with an increased concentration CDs induce localized hyperpyrexia to ablate tumors Exhibit higher MRI/CT imaging contrast enhancement of tumor sites	163
BC	ID@E-MSNs	PTT	Retain the photothermal effect of ICG and cytotoxicity of DOX Produce hyperthermia to collapse E-MSNs nanovehicles, accelerate drug release, and induce tumor ablation under 808 nm near-infrared irradiation Inhibit the growth and metastasis of tumor	103
BC/CC/leukemia	Exo-DOX-Fe3O4@PDA-MB	PTT	Enable enrichment of the exosomes at the tumor site by external magnetic field guidance. Utilize localized hyperthermia to trigger the release of cargoes Target the miR-21 for both imaging and gene silencing Kill the cancer cells via DOX	106
GBM	CAT@SiO2-ICG	SDT	Possess efficient BBB penetration and good cancer cell-targeting capability Relieve tumor hypoxia	50
PC	ExoCe6+R848	SDT	Enhanced R848-mediated DCs maturation Reprogram macrophages from M2 phenotype to M1 phenotype Activate effector T cells Revert the immunosuppressive TME	90
BC/CRC	EXO-DVDMS	SDT	Trigger DVDMS relocation Initiate multiple cells death-signaling pathways Facilitate simultaneous imaging and tumor metastasis inhibition	231
BC	SBC-EV(ICG/PTX)	SDT	Improve the cellular uptake of ICG Release the PTX in response to acidic pH in the endo/lysosomes Burst exosome membranes by CO2 bubbles	75
BC	FA-ExoICG	SDT	Improve aqueous stability Promote cellular uptake of ICG Increase ROS generation Trigger sonotoxicity against cancer cells	232
BC	Let-7 miRNA -AS1411-Exo/VEGF siRNA -AS1411-Exo	GT	Inhibit malignant growth of cancer cells by reducing MYC and RAS expression	201
BC	HER2/Neu-siRNA TPD52-Exo	GT	Bind specifically to HER2/Neu Deliver siRNA molecules against TPD52 gene	206
BC	miR-379 -Exo	GT	Elevate miR-379 Reduce COX-2 mRNA and protein in vitro and in vivo	214
BC	uPA-eEV-PNCs	GT	Overexpress miRNA-10b and miRNA-21 Alleviate chemoresistance and metastatic potential	175
BC	293-miR-XS-HER2	GT	Block HER2 synthesis Adhere to HER2 on the surface of cancer cells	216
BC/ Leukemia	ASOCXCR4+EGFR+EpCAM -Exo	GT	Knockdown oncogenic miR-125b Target to CXCR4	211
BC/l LC	miRNA-231-Exo	GT	Recognize lung cancer cells in blood Escape from the immune surveillance system in vitro Suppress lung cancer cell proliferation and migration Interrupt the PTEN/PI3K/AKT pathway	213
BC/HCC/CC	CRISPR-Cas9-Exo	GT	Downregulate GFP or WNT10B Reduce WNT10B in vitro, ex vivo, and in vivo	221
OS	miR-317b-5b-Exo	GT	Enhance the internalization of miR317b-5b in tumor cells Suppress cell viability, proliferation, migratory and invasive capability Promote apoptosis	204
OS	cRGD-Exo-MEG3	GT	Unclear	205
OS	miR-101-Exo	GT	Reduce BCL6 mRNA and protein Target BCL6 via miR-101	219
LC	Hybrid Lipid-Exo	GT	NA	202
LC	β-catenin siRNA-Exo	GT	Bind to EpCAM Decrease β-catenin expression and proliferation	210
HCC	miR-26a-Exo	GT	Bind selectively to cancer cells via the scavenger receptor class B type 1–Apo-A1 complex Promote the internalization by receptor-mediated endocytosis Upregulate miR-26a expression Decrease the rates of cell migration and proliferation	212
HCC	HN3LC9-293exo	GT	Target GPC3 with high affinity Direct Cas9 protein to the site of IQGAP1 in the genomic locus for efficient cleavage	209
HCC	miR-125b-Exo	GT	Overexpress miR-125b in HCC cells Induce cell cycle arrest Inhibit proliferation, migration, and invasion	207
GC/CRC/ LC	CXCR4high Exo/si-Survivin	GT	Bind to the highly expressed stromal cell-derived factor-1 (SDF-1) on the tumor surface Knock down the Survivin gene in tumor cells in vivo and thereby inhibiting tumor growth	217
PC	PSMA-EMs	GT	Trigger PSMA-mediated endocytosis Release drug intracellularly	215
PC	SIRT6 siRNA-Exo	GT	Activate multiple cancer-related signaling pathways, especially the Notch pathway Silence SIRT6 Inhibit tumor growth and metastasis	48
LC	sgRNA:Cas9-Exo	GT	Enrich sgRNAs and Cas9 proteins in exosomes using GFP-binding nanobody	218
PDAC	KrasG12D RNAi-Exo	GT	Knockdown KrasG12D via siRNA or shRNA	60
GBM	MNP@BQR@ANG-EXOsiGPX4	GT	Accumulate in the brain under local magnetic localization Trigger transcytosis Target GBM cells by recognizing the LRP-1 receptor Trigger ferroptosis by the combined triple actions of the disintegration of dihydroorotate dehydrogenase and the glutathione peroxidase 4 ferroptosis defense axis with Fe3O4 nanoparticle-mediated Fe2+ release	127
GC	RGD-Exo-circDIDO1	GT	Inhibit GC progression by regulating the expression of the signal transducer inhibitor SOSC2 through sponging miR-1307-3p	208
Glioma	miR-29a-3p-Exo	GT	Inhibit migration and VM formation Target ROBO1 via miR-29a-3p	220
BC	IL4R-Exo(si/mi)	IT	Foster M1 polarization by NF-B p50 siRNA and miR-511-3p Target the IL4R of TAMs	194
BC	aCD47/aSIRPα-Exo	IT	Cleave the benzoic-imine bonds of exosomes nanobioconjugates in the acidic TME Block SIRPα on macrophages and CD47 Transit the macrophages from pro-tumoral M2 to antitumoral M1	193
BC	GEMINI-Exos	IT	Redirect and activate T cells toward killing EGFR-positive TNBC	179
BC	HPV-E7-Exo	IT	Trigger a stronger antigen cross-presentation in both B- lymphoblastoid cell and monocyte-derived immature DCs Increase TAA-specific CD8+ T cell	225
BC	HELA-Exos	IT	Induce ICD in breast cancer. Activate cDC1s in situ Cross-prime tumor-reactive CD8+ T-cell response	230
BC	SMART-Exos	IT	Target T-cell CD3 and breast cancer-associated HER2 receptors dually Redirect and activate cytotoxic T cells toward attacking HER2-expressing breast cancer	56
BC/NSCLC	EGFR / HER2 CAR -Exo	IT	Express a high level of cytotoxic molecules without PD1	182
BC/ LC	HER2/neu/Nefmut -Exo	IT	Target antigen-specific CD8+ T lymphocytes Activate HER2-directed CTL activity	224
BC/Lymphoma/Melanoma	aMT-exos	IT	Prime T-cell activation in both the classical antigen-presenting cell-induced immunostimulatory manner and a unique “direct exosomes interaction” manner Ameliorate immunosuppression	92
BC/CRC/NSCLC/Melanoma	eNVs-FAP	IT	Induce strong and specific CTL immune responses against tumor cells and FAP + CAFs Reprogram the immunosuppressive TME Promote tumor ferroptosis by releasing interferon-gamma (IFN- γ) from CTLs and depleting FAP + CAFs.	51
Melanoma	CpG-SAV-exo	IT	Activate DC2.4 cells Enhance tumor antigen presentation capacity Exhibit stronger antitumor effects in vivo	86
Melanoma	Exo-OVA-aCD3/aEGFR	IT	Activate endogenous T cells efficiently Crosslink with cancer cells Upregulate PD-L1 expression	55
LC	Nefmut/E7-Exo	IT	Trigger CD8+ T-cell immune response	222
B-LCL	HPV-E6-Exo	IT	Trigger a stronger antigen cross-presentation in both B- lymphoblastoid and monocyte-derived immature DCs Increase TAA-specific CD8+ T cells	223
Myeloma	EXOHSP	IT	Stimulate maturation of DCs Activate Th1 cell responses, and more efficient P1A-specific CD8+ CTL responses	93
CML	CoEX-A2s	IT	Stimulate antigen-specific CD8+ T cells both directly and indirectly via CoEX-A2 crossdressed cells Generate HCMV pp65-specific and MART1-specific CD8+ T cells as DEX in vitro	227
HCC	DEXP&A2&N	IT	Promote recruitment, accumulation and activation of DCs Enhance cross-presentation of tumor neoantigens and de novo T-cell response. Increase immunological memory against tumor re-challenge	183
Myeloma	EXOTNF-a	IT	Induce more efficient P1A-specific CD8þ T-cell response	229
CRC	ExoASO-STAT6	IT	Silence STAT6 expression in TAMs Remodel the TME Generate CD8+ T cell-mediated adaptive immune response	88

CC cervical cancer, OS osteosarcoma, PC prostate cancer, GBM glioblastoma, PDAC pancreatic ductal adenocarcinoma, GC gastric cancer, BC breast cancer, NSCLC Non-small cell lung cancer, LC lung cancer, CML chronic myelogenous leukemia, HCC hepatocellular cancer, CRC Colorectal cancer, STAT6 signal transducer and activator of transcription 6, IT immune therapy, CTL cytotoxic T, lymphocyte, ICD immunogenic cell death, TNBC triple-negative breast cancer, TAMs tumor-associated macrophages, GBM glioblastoma, GFP green fluorescent protein, PSMA prostate-specific membrane antigen, GT gene therapy, BCL6 B cell lymphoma, CXCR4 CXC chemokine receptor type 4, HER2 human epidermal growth factor receptor 2, ICG Indocyanine green, SDT Sonodynamic therapy, BBB blood-brain barrier, DCs dendritic cells, TAA tumor-associated antigen, PTT photothermal therapy, PDT Photodynamic therapy, ROS reactive oxygen species, TME tumor microenvironment, RT radiotherapy, 5-FU 5-Fluorouracil, MR magnetic resonance, GNR gold nanorods, PTX paclitaxel, DTX docetaxel, CT Chemotherapy, GNP gold nanoparticle, SIRPα signal regulatory protein α, DOX doxorubicin