Many substantial hurdles must be solved for in vivo or in vitro clinical translation of the Polydopamine (PDA)-based nanomaterials. Excessive accumulation of residual unreacted DA and specific metabolites (DA or other small molecules) of PDA in vivo may trigger a possible syndrome of dopamine dysregulation characterized by addictive behaviour, as DA may act as an endogenous neurotoxin when its vesicular sequestration is dysregulated. PDA nanoparticles' activity and long-term stability should be fully studied for in vivo applications aside from probable toxicity. According to the findings, PDA's strong reactivity with numerous functional groups (catechol, quinone, and amine) is comparatively favorable, but in mild circumstances it may have negative effects on the organism owing to direct alcohol interactions. More crucially, the charged, moist adhesive PDA has a high affinity for protein attachment, which might be a major defect in the blood contact process. Direct blood contact with these PDA-based nanomaterials with high specific surface area would result in fast protein adsorption, the establishment of a "protein corona" within minutes, and increased thrombus formation risk. In vitro applications, on the other hand, can prevent the threat of detrimental cell or tissue effects. New rules, theories and processes on structure property performance relationships may be developed by researching the in vivo bioapplications of the above-mentioned PDA nanoarchitectures, possibly leading to fundamental and useful insights into in-vitro material translations. Despite the fact that major impediments to structural control persist, it is predicted that in the future, electron coupling will bring new answers to challenges of improved illness diagnosis and therapy.