Multifunctional approaches of cubosome-integrated thermoresponsive gels for intranasal brain targeting: Innovations, therapeutic potential, and challenges
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Date
2026
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Abstract
Neurodegenerative disorders, such as cognitive disabilities and dementia, have nowadays become a global
burden, distressing millions of elderly people worldwide. It is characterized by progressive loss of neurons in the
central nervous system, affecting higher cortical centers and ultimately impacting the social life of the patients.
Conventional treatment approaches to such neurological complications primarily involve systemic drug delivery
through either oral or parenteral routes of administration. However, limited brain bioavailability due to the
restrictive properties of the blood-brain barrier, systemic side effects, biotransformation of the drug, and limited
ability to maintain therapeutic concentrations in the CNS pose a challenge in targeted therapy. In recent years,
cubosomes, nanostructured lipid-based carriers of an internally bi-continuous cubic phase, have emerged as a
novel drug delivery system, which are capable of encapsulating both hydrophilic and lipophilic drugs. These
unique structured nanocarriers possess favourable physical properties, including high surface area and ther
modynamic stability, which make them a potential tool for controlled and targeted drug delivery systems. With
intranasal administration, cubosomes offer the ability to bypass the BBB due to the use of the olfactory and
trigeminal neural pathways, achieving direct brain targeting of the therapeutics. Thus, this review aims to
provide an overview of the nose-to-brain transport mechanisms, based on the anatomical and physiological basis
following intranasal delivery of cubosomes integrated into thermoresponsive in situ gels. The review also focuses
on their potential therapeutic applications in the treatment of neurodegenerative diseases. In addition, the re
view also presents formulation challenges and strategies to address them, providing insight into the future
possibilities of cubosome-based gels as a new non-invasive brain-targeted therapy.