Background

Carica papaya L. leaf extract has long been recognized for its therapeutic potential in dengue-associated thrombocytopenia through enhancement of platelet production and inhibition of dengue viral proteases. However, its oral delivery is hindered by poor bioavailability, instability of phytochemicals, and lack of optimized delivery platforms.

Novelty and Objective

This study reports, for the first time, the development and optimization of an oral pro-transferosome tablet of Carica papaya leaf extract, enabling improved bioavailability, storage stability, and therapeutic efficacy. Furthermore, it elucidates a new mechanistic hypothesis the complementary and differential molecular targeting of ALOX-12 by carpaine and PTAFR by quercetin providing deeper insight into its platelet-enhancing and anti-dengue actions.

Methods

Using a Box-Behnken Design, three critical formulation variables phospholipid concentration, edge activator content, and extract-to-lipid ratio were optimized for entrapment efficiency, particle size, and zeta potential. The resulting tablets underwent physicochemical characterization, vesicle morphology assessment, tablet quality evaluation, in vitro drug release, and accelerated stability testing. Molecular docking was performed to determine binding affinities of carpaine and quercetin to platelet-production-related proteins (ALOX-12, PTAFR) and dengue viral proteases.

Results

The optimized oral pro-transferosome tablets achieved 87.4% entrapment efficiency, 145.7 nm particle size, and − 32.5 mV zeta potential, indicating a stable vesicular system. Morphology confirmed nanosized spherical vesicles with narrow distribution. Tablet evaluation showed consistent weight uniformity, optimal hardness, low friability, and rapid disintegration (~ 4.2 min). In vitro release revealed sustained carpaine release (88% over 12 h), supporting prolonged therapeutic effect. Docking revealed strong binding of carpaine to ALOX-12, while quercetin showed high affinity to PTAFR and negligible interaction with ALOX-12, suggesting dual but distinct platelet-regulating pathways.

Conclusion

This is the first report of an oral pro-transferosome tablet formulation of Carica papaya leaf extract, combined with the discovery of distinct molecular targets for its key bioactives. These findings not only establish a novel, clinically relevant delivery system but also propose a new mechanistic basis for its efficacy against dengue-induced thrombocytopenia.

By Kiran Sai Maccha, Nagashubha Bobbarjang, Naresh Babu C, Pallvi R, Roopeswari Yellaboyala, Sameera Yasmin G, Sainath B & Muthyalu C