Cell-Penetrating Peptide-engineered Solid Lipid Nanoparticles for Enhanced Endocytotic Internalization and Transdermal Penetration

초록

Efficient drug delivery across biological barriers remains a fundamental challenge, particularly for rigid nanocarriers whose penetration mechanisms are poorly understood. Here we demonstrate that Laminin-332-functionalized solid lipid nanoparticles (SLNLam) overcome cellular barriers through receptor-mediated endocytosis and achieve substantial transdermal penetration. SLNLam particles, engineered via site-specific thiol-maleimide chemistry, maintain crystalline structural integrity while enabling precise surface modification at controlled peptide densities. Biolayer interferometry reveals that binding kinetics correlate directly with alpha 3 beta 1 integrin surface density, confirming molecular recognition as the primary interaction mechanism. Dissipative particle dynamics simulations elucidate interaction energetics, demonstrating adhesion-dependent membrane fusion behavior. Mechanistic studies in HaCaT keratinocytes establish lipid raft-mediated endocytosis as the predominant uptake pathway, with methyl-beta-cyclodextrin treatment significantly attenuating internalization while ATP-dependent and clathrin-mediated pathways remain unaffected. Ex vivo analysis using porcine skin demonstrates concentration-dependent cargo delivery enhancement, with mathematical modeling revealing exponential decay kinetics (I(z) = I 0 e -kz ) where penetration constants are proportional to Laminin-332 density. These findings establish that receptor-targeted surface engineering enables efficient barrier penetration through specific adhesion mechanisms, providing a robust framework for advancing rigid nanocarrier delivery systems with transformative implications for pharmaceutical and cosmetic applications.

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