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The present study explores the potential of polyelectrolyte-coated liposomes for improving the oral deliverability of doxorubicin (Dox). As a part of formulation strategy, stearyl amine was selected as a formulation component to provide positive charge to liposomes, which were subsequently coated with anionic poly(acrylic acid) (PAA) followed by coating of cationic polyallyl amine hydrochloride (PAH) in a layer by layer manner and led to the formation of a robust structure "layersomes". Optimization of various process variables were carried out, and optimized formulation was found to have particle size of 520.4 ± 15.0 nm, PDI of 0.312 ± 0.062, ζ potential of +30.4 ± 5.32 mV, and encapsulation efficiency of 63.4 ± 4.26%. Layersomes were not only stable in simulated gastrointestinal fluids but also presented sustained drug release (∼35%) as compared to both Dox-liposomes and PAA-Dox-liposomes (∼67%), the release pattern being Higuchi kinetics. The in vivo pharmacokinetics studies revealed about 5.94-fold increase in oral bioavailability of Dox as compared to free drug. In vivo antitumor efficacy in a DMBA-induced breast tumor model further exhibited significant reduction in the tumor growth as compared to control and IV-Dox, while results were comparable to IV-LipoDox. Layersomes also exhibited a marked reduction in cardiotoxicity in comparison with IV-doxorubicin and IV-LipoDox (marketed formulation), as evidenced by the reduced levels of malondialdehyde (MDA), lactate dehydrogenase (LDH), and creatine phosphokinase (CK-MB) and increased levels of glutathione (GSH) and superoxide dismutase (SOD). The reduced cardiotoxicity of layersomes was further confirmed by comparative histopathological examination of heart tissue after treatment with various formulations. The positive results of the study strengthen our expectation that the developed formulation strategy can be fruitfully exploited to improve the oral deliverability of poorly bioavailable drugs and can open new vistas for oral chemotherapy.