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Tretinoin (TRE) is a widely used retinoid for the topical treatment of acne, psoriasis, skin cancer and photoaging. Despite unmatchable efficacy, it is associated with several vexatious side effects like marked skin erythema, peeling and irritation, eventually leading to poor patient compliance. Its photo-instability and high lipophilicity also pose challenges in the development of a suitable topical product. The present study, therefore, aims to develop biocompatible lipid-based nanocarriers of TRE to improve its skin delivery, photostability, biocompatibility and pharmacodynamic efficacy. The TRE-loaded liposomes, ethosomes, solid lipid nanoparticles (SLNs) and nanostructured lipidic carriers (NLCs) were prepared and characterized for micromeritics, surface charge, percent drug efficiency and morphology. Bioadhesive hydrogels of the developed systems were also evaluated for rheological characterization, photostability, ex vivo skin permeation and retention employing porcine skin, and anti-psoriatic activity in mouse tail model. Nanoparticulate carriers (SLNs, NLCs) offered enhanced photostability, skin transport and anti-psoriatic activity vis-à-vis the vesicular carriers (liposomes, ethosomes) and the marketed product. However, all the developed nanocarriers were found to be more biocompatible and effective than the marketed product. These encouraging findings can guide in proper selection of topical carriers among diversity of such available carriers systems.