AbstractNeurodegenerative diseases (NDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD) are an accelerating global health problem as life expectancy rises worldwide. Despite their significant burden in public health systems to date, the existing treatments only manage the symptoms without slowing down disease progression. Thus, the ongoing neurodegenerative process remains untreated. Moreover, the stronghold of the brain—the blood–brain barrier (BBB)—prevents drug penetrance and dwindles effective treatments. In the last years, nanotechnology‐based drug delivery systems (DDS) have become a promising approach to target and treat these disorders related to the central nervous system (CNS). PLGA based nanoparticles (NPs) were the first employed DDS for effective drug delivery. However, the poor drug loading capacity and localized immunogenicity prompted the scientific community to move to another DDS such as lipid‐based NPs. Despite the lipid NPs' safety and effectiveness, their off‐target accumulation together with the denominated CARPA (complement activation‐related pseudo allergy) reaction has limited their complete clinical translation. Recently, biological NPs naturally secreted by cells, termed as extracellular vesicles (EVs) have emerged as promising more complex biocompatible DDS. In addition, EVs act as dual players in NDs treatment, as a “cell free” therapy themselves, as well as new biological NPs with numerous characteristics that qualify them as promising carriers over synthetic DDS. The present review aims to display advantages, drawbacks, current limitations and future prospective of the previously cited synthetic and biological DDS to enter the brain and treat one of 21st century most challenging diseases, NDs.This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease