Sponges are benthic filter-feeder invertebrates capable to produce a variety of high value bioactive compounds. Nevertheless, exploitation of sponges as bio-factories requires scalable and sustainable strategies to supply sponge biomass without threatening wild natural populations and to minimize the consumption of toxic organic solvents in metabolites extraction and purification procedures. Sponges farming in integrated facilities nearby fish mariculture cages represents a highly efficient strategy combining the production of sponge biomass with bioremediation. Here we report the results of the in situ rearing of the keratose sponge Sarcotragus spinosulus developed within three years in an innovative Integrated Multi-Trophic Aquaculture system in the Gulf of Taranto (Southern Italy, Mediterranean Sea), capable to supply large-scale sponge biomass with a minimal impact on wild populations. Moreover, we demonstrate the proof of concept that it is possible to produce polyprenyl hydroquinones, selected as well-known bioactive model metabolites, in good yields, high purity degree and low organic solvent consumption, by means of an innovative protocol based on the combination of supercritical carbon dioxide fluid extraction and gel permeation chromatography. Such a combination of eco-friendly techniques paves the way to eco-sustainable supply of bioactive compounds from marine organisms highly profitable in terms of working times, costs, solvents, and energy saving.