Small extracellular vesicles expressing a dominant negative AMPK alpha 1 mutant for use in the treatment of obesity

A method for treatment of obesity, comprising systemically administering to a subject in need thereof a population of small extracellular vesicles (sEVs) capable of significantly decreasing the activation levels of AMP-activated protein kinase (AMPK) in SF1 expressing neurons located in the ventromedial nucleus of the hypothalamus (VMH) in comparison to the activation levels of AMPK in untreated SF1 expressing cells, without said decrease being significantly reduced in other SF1 expressing tissues selected from the group consisting of adrenal glands, testicles, and pituitary gland;

• wherein said population of sEVs comprises at least one polynucleotide encoding a dominant negative AMP-activated protein kinase alpha 1 (AMPKα1-DN) mutant protein, wherein the amino acid sequence of the AMPKα1-DN mutant protein consists of SEQ ID NO:
• 1,
• wherein said AMPKα1-DN mutant protein is operably linked and under the control of a steroidogenic factor 1 (SF1) promoter that has at least 98% sequence identity with SEQ ID NO:
• 3, and
• wherein the sEVs are engineered to express in their outer membrane at least one fusion protein comprising a neurotrophic rabies virus (RVG) peptide fused to lysosome-associated membrane protein 2b.