The association of numerous advantages of natural active compounds (from vegetal and herbs) and endogenous lipid in the same delivery system is a straightforward approach for the development of safe and better tolerated anti-obesity therapy. In the present study we envisage a novel concept for obesity therapy, devoted to the development of innovative lipid nanostructured formulas with improved gastric tolerability and enhanced specificity in adipose cells targeting. For this purpose, an anti-obesity herbal active from red pepper extract - Capsaicin (Cap) and an endogenous lipid regulator of appetite - oleoylethanolamide (OEA) or a structural analogue of OEA - Phenylalaninol oleamide (PAO), are simultaneously integrated within the same delivery system - nanostructured lipid carriers (NLC) prepared with linseed oil that has anti-inflammatory and hypotriglyceridemic properties. The NLC-OEA/PAO-Cap presented mean diameters under 200 nm, size that allow an efficient uptake of actives by enterocytes and lead to an extended biological action of all actives - Cap, OEA/PAO and linolenic acid. NLC revealed a polidispersity index ranging from 0.16 to 0.22, which represents a narrow dispersion around mean size and suggests an adequate unimodal behavior. The two types of NLC co-loaded with Cap and OEA/PAO were both negatively charged, with zeta potentials of -42.8 mV and -58.5 mV that offered a guarantee for an excellent stability of NLC in time. Despite to the competition between the accommodations of both actives into the lipid core of nanocarriers, the entrapment efficiency exceeds 92% for OEA/PAO and is ranged between 71 and 82% for Cap. In the presence of NLC-OEA/PAO-Cap, ABTS+⁎ inhibition proceeded in a Capsaicin concentration dependent manner and was dependent on the type of NLC formulation. A remarkable radical-scavenging activity against ABTS+⁎ was determined for Cap and OEA based-NLC. The in vitro release demonstrated that NLC played an important role on the delay of Cap dissolution; the NLC have ensured a slow release of Cap, eg only 21% Cap was released after 24 h of in vitro experiments. The in vivo pharmacological evaluation has revealed that the NLC-OEA/PAO-Cap treatment resulted in a body weight decrease and improves the lipid and glucose profile, as compared to the obese mice batch. Obesity mice treated with NLC-OEA exhibited a weight loss of ~15% and ~10% weight loss for NLC-POA, after 10-days treatment. Administration of NLC-OEA/PAO-Cap to the Albino Swiss mice led to significant decrease of glucose level (e.g. 117.4 mg/dL for NLC-OEA-Cap treated mice versus 213.9 mg/dL for obese mice batch) and exhibited a desired decrease effect of triglyceride (e.g. 71.1 mg/dL for NLC-OEA-Cap versus 129.5, for obese batch). Moreover, the cholesterol values have been lowered to almost half from the value determined for the control batches. Overall, study highlights that using appropriate lipid mediators in association with an herbal anti-obesity active, both formulated into lipid nanocarriers, could enhance the therapeutic response in the obesity treatment.