An AI-assisted designed supramolecularly engineered nanoplatform reverses pigmentation by triggering an ineffective compensatory melanin production program

The clinical applications of natural compounds are limited by their inherent physicochemical properties. This study reports a hierarchical supramolecular engineering strategy for constructing a dual-assembly nanosystem for the treatment of skin hyperpigmentation. Using an AI-assisted computational screening model, tranexamic acid was identified as a suitable molecular partner of the hydrophobic and active, baicalin. Subsequent dual assembly processes yielded a stable hybrid nanoplatform (DHBTC) that enhanced the solubility and delivery efficiency of baicalin. Single-cell transcriptomics revealed an unexpected mechanism of "functional inhibition"; despite the depigmenting efficacy of DHBTC, the melanogenesis-related gene network in melanocytes was upregulated. This was identified as compensatory transcriptional feedback triggered by drug-induced autophagy. DHBTC functionally inhibits pigment accumulation by accelerating melanosome degradation, which elicits ineffective transcriptional activation as the cell attempts to restore homeostasis. Furthermore, the platform remodeled the cutaneous immune microenvironment toward an anti-inflammatory state. This study presents a strategy for designing drug delivery systems, from computational prediction to supramolecular assembly, and describes a therapeutic mechanism based on the modulation of post-translational and organellar homeostasis. This study presents a platform strategy for drug delivery system design, spanning from computational prediction to supramolecular construction. The strategy first employed an AI-driven reverse design to screen and predict tranexamic acid as the ideal molecular partner for the hydrophobic baicalin. Subsequently, through hierarchical supramolecular engineering, the components were self-assembled and encapsulated with cyclodextrin to build a novel nanoplatform (DHBTC). This platform overcame key biopharmaceutical barriers, increasing baicalin's solubility 608-fold and enhancing penetration. Mechanistically, it effectively reversed hyperpigmentation by accelerating autophagy-mediated melanosome clearance and remodeling the skin's immune microenvironment toward an anti-inflammatory state. • An AI-driven reverse design strategy guided the hierarchical supramolecular assembly, yielding the DHBTC nanoplatform that addresses key delivery challenges of baicalin, including its stability, solubility, and transdermal permeability. • Single-cell transcriptomics revealed a novel functional inhibitory mechanism, wherein DHBTC accelerates autophagy-mediated melanosome clearance, triggering a compensatory yet ineffectual transcriptional upregulation of the melanogenesis program. • DHBTC reverses hyperpigmentation via a dual therapeutic strategy: blocking pigment accumulation at the post-translational level while simultaneously remodeling the skin immune microenvironment toward a homeostatic anti-inflammatory state.