Disease modifying treatment of hereditary transthyretin amyloidosis with polyneuropathy in Germany - expert consensus of the German society of amyloid diseases (DGAK) and the German neurological socie

When exosomes were first discovered in 1981, they were thought to be merely metabolic waste products of maturing red blood cells. However, as research on extracellular vesicles (EVs) has progressed, exosomes have been redefined as nanoscale membrane vesicles primarily formed via the endosomal pathway and released following fusion of multivesicular bodies with the cell membrane []. They are widely present in nearly all biological fluids and tissues [,], including blood, urine, saliva, and breast milk. As endogenous intercellular communication carriers, exosomes can transfer molecular substances, such as proteins, lipids, and nucleic acids, from donor cells to recipient cells []. Compared to synthetic nanocarriers, exosomes demonstrate unparalleled natural advantages in clinical drug delivery due to their higher biocompatibility and lower immunogenicity []. Exosomes also possess the innate ability to penetrate complex biological barriers such as the blood–brain barrier (BBB) [] and can reduce tumor multidrug resistance by bypassing the P-glycoprotein efflux system []. Exosomes have become a promising platform for precision medicine in clinical practice []. To further enhance their targeting precision, loading efficiency, and intracellular delivery capacity, researchers have developed various engineered exosomes using advanced technologies such as genetic engineering of donor cells [], in vitro chemical functionalization [], physical drug loading [], and biohybridization []. These engineered exosomes have shown excellent efficacy in various aspects such as tumor treatment, brain-targeted delivery, RNA and protein delivery, and immune regulation []. However, the biomedical performance of engineered exosomes should not simply depend on their accumulation or uptake in target cells but also be evaluated by whether they can achieve effective functional delivery and produce expected biological effect [–]. After internalization, cargos may remain trapped in endosomes, be degraded by lysosomes, recycle back to the plasma membrane, or reach functional intracellular sites. Without standardized qualitative and quantitative evaluation strategies, labeling artifacts, nonspecific cell association, and misunderstandings of endocytic pathways may lead to misjudgments of delivery efficiency and therapeutic potential.