**1. Introduction**

*Euphausia superba*, commonly known as krill, is a small marine crustacean from the Antarctic Ocean that plays an important role in the marine ecosystem, serving as feed for most fish [1]. Although measuring krill biomass is difficult, it has been estimated at approximately 379 million metric tons. The Commission for the Conservation of Antarctic Marine Living Resources (CCAMLR) has set a catch limit of 620,000 tons per year to protect the marine ecosystem [2]. Nevertheless, the annual catch is around 250,000 tons, indicating use below the established limits, which is probably due to the difficulty in conserving krill and its fragility [3].

In fact, krill is commonly used in the sport fishing market as well as in the aquaculture industry. However, in recent years, krill has been successfully investigated for its role as a nutritional supplement to improve human health. This is because krill is rich in nutrients, including vitamins A and E, minerals, n-3 polyunsaturated fatty acids (n-3 PUFAs), phospholipids (PLs), astaxanthin and flavonoids [4].

**Citation:** Colletti, A.; Cravotto, G.; Citi, V.; Martelli, A.; Testai, L.; Cicero, A.F.G. Advances in Technologies for Highly Active Omega-3 Fatty Acids from Krill Oil: Clinical Applications. *Mar. Drugs* **2021**, *19*, 306. https:// doi.org/10.3390/md19060306

Academic Editors: Maria do Rosário Domingues and Philippe Soudant

Received: 21 April 2021 Accepted: 21 May 2021 Published: 26 May 2021

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Particular attention has been paid to lipid content (0.5% to 3.6%) [5], including phospholipids (30–65%) and triglycerides, while fish oil is only comprised of triglycerides. The main phospholipid in krill oil is phosphatidylcholine, with 40% of the total fatty acids bound to phosphatidylcholine being eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) [6]. The EPA and DHA omega-3 fatty acids found in krill oil have shown several useful pharmacological properties in the management of numerous chronic dysfunctions, including cardiovascular, neurological and inflammatory diseases, as well as the prevention of cancer and promoting gut microbiota health [7–10]. In this regard, supplementation with krill polyunsaturated fatty acids may be a natural way to relieve the symptoms of these conditions, potentially in combination with conventional therapies [11]. EPA and DHA from krill oil have also shown higher bioaccessibility than other forms of n-3 PUFAs (ethyl-ester and re-esterified omega 3), demonstrating similar benefits, but at smaller dosages [12].

Krill oil was authorized in 2008 by the U.S. Food and Drug Administration (FDA) as GRAS (Generally Recognized as Safe), was approved in Europe by EFSA as a novel food in 2009 and was also approved in China in 2014. Finally, krill oil was authorized by EFSA for pregnant and lactating women in 2014.

This review aims to provide an overview of the chemical composition, bioavailability and bioaccessibility, mechanism of actions, classic and non-conventional extraction techniques, health benefits and current applications of krill oil underlying the future perspectives of this nutraceutical.
