Table 4.

Summary of review articles on PDENs in biomedical approaches.

Potential Target Tissue or Disease	Prospects	Challenges and Issues	Refs.
Periodontitis	PDENs could steadily carry drugs for oral mucosal delivery to modulate oral immunity to periodontopathogen	PDENs could only load small amounts of drugs, with an unclear mechanism of cellular uptake as it may vary per extraction batch	[69]
Colitis, tumor, liver diseases, skin diseases, periodontitis	PDENs could act as a drug-delivery system to deliver RNAs and lipids for the inhibition of inflammation genes, as well as bacterial and tumor growth	No clarity on quality control and evaluation systems, stability, biomarker confirmation, and biochemical characterization	[204]
Unspecified	Easier large-scale mass production for their large biodiversity with minimal cytotoxicity for drug-delivery system	Elusive internalization mechanisms and unclarity of specific receptors and ligands for PDENs. Biosafety and toxicity of genetic transfer are unclear	[205]
Intestine	PDEN-derived miRNAs could modulate gut microbiome, intestinal permeability, and mucosal immunity	High variability of results in studies, due to the lack of consensus regarding PDEN-derived miRNAs	[206]
Inflammatory bowel disease, liver disease, cancer	PDENs could mediate interspecies communications to exert their antioxidant, anti-inflammatory, and regenerative activities	Low amount and different kinds of PDEN-derived proteins compared to MSC-derived exosomes	[207]
Colitis	PDENs could transfer exogenous drugs or endogenous cargo to epithelial and bacterial cells for their stability in intestinal fluid	Standardization on mass producing and purification techniques	[72]
Unspecified	PDENs stability in the digestive system make it a promising functional food to alleviate inflammation	Instability during isolation and processing with unclear proteomic profiling	[21]

Abbreviations: PDENs = plant-derived exosome-like nanoparticles; miRNA = micro-RNA; MSC = mesenchymal stem cell.