Enhancing effect and safety assessment of borneol on the oral absorption of sub-100 nm PLGA nanoparticles

Overcoming the gastrointestinal barrier remains a major challenge for oral nanoparticle (NP) drug delivery systems. Here, we evaluate borneol as a permeation enhancer for improving the oral absorption of intact poly(lactic-co-glycolic acid) (PLGA) nanoparticles with different mean sizes (50–300 nm) and assess its long-term safety. In vitro, sub-100 nm nanoparticles (NPS-S) exhibited superior cellular uptake and transport across Caco-2 monolayers compared to their larger counterparts. Borneol selectively and concentration-dependently enhanced the absorption of NPS-S, mechanistically linked to the promotion of caveolae-mediated endocytosis and the reversible modulation of tight junctions, as evidenced by a decrease in transepithelial electrical resistance (TEER) and occludin disruption. Utilizing an aggregation-caused quenching (ACQ) probe for specific tracking of intact NPs, in vivo studies confirmed that borneol significantly enhanced the gastrointestinal retention, absorption and systemic distribution of intact NPS-S. A comprehensive toxicological evaluation, including a 30-day rat study, demonstrated that borneol did not induce cytotoxicity, inflammation, or tissue damage at daily doses up to 270 mg/kg. Our findings establish borneol as a safe and effective oral permeation enhancer for intact nanocarriers, offering a viable strategy to enhance the oral bioavailability of therapeutics, particularly those encapsulated within small-sized NPs.