Work

AI-guided design of a CXCR4-targeted core-shell nanocarrier for co-delivery of berberine/paclitaxel in cancer therapy

Year: 2025

Type: article

Abstract: An integrated three-step artificial-intelligence (AI) workflow was used to accelerate the design of a CXCR4-targeted, dual-drug nanocarrier for colorectal-cancer therapy. First, the MD-Syn platform screened 38 approved oncology agents across six human colorectal-cancer cell lines (HCT116, HT29, LoVo, RKO, SW620, SW837) and identified paclitaxel (PTX) as the compound with a > 0.9999 probability of synergy with (BBR). Second, a dual peptide-discovery pipeline that combined CABS-dock flexible docking with AlphaFold-multimer/NeuroSNAP-AI scoring yielded a high-affinity 9-mer stromal-cell-derived factor-1 fragment (CXCR4-binding peptide, CXCR4BP; ipTM = 0.95). The peptide was conjugated to DSPE-PEG₂₀₀₀ to form a targeting liposome (CXCR4BPL). Third, FormulationAI predicted that loading PTX into the CXCR4BPL shell and BBR into phosphonate-functionalized mesoporous silica nanoparticles (FMSNs) would maximize encapsulation. A one-pot self-assembly gave FMSN(BBR)-CXCR4BPL(PTX) core–shell nanocarrier (~ 130 nm) with experimental entrapment efficiencies of 78.8 ± 1.9% for BBR and 75.2 ± 2.4% for PTX and sustained co-release over 72 h at pH 7.4. In CXCR4-positive CT26 cells, the core-shell nanocarrier curtailed scratch-wound closure by ~ 94% and reduced metabolic viability to 36% at 72 h, markedly outperforming free drugs and non-targeted controls. A single intravenous dose delivering 5 mg/kg BBR equivalent in CT26-bearing mice restricted tumor volume and mass to ~ 15% and ~ 13% of PBS controls, normalized splenomegaly four-fold, and produced pronounced decreases in Ki-67 and CD31 with increased TUNEL positivity, all without body-weight loss or organ pathology. These results demonstrate that AI-guided synergy scouting, ligand discovery and drug-allocation modelling can be seamlessly combined with modular nanocarrier engineering to generate a high-payload, CXCR4-targeted PTX/BBR therapy that delivers potent antitumor efficacy alongside excellent systemic tolerance, offering a transferable blueprint for next-generation combination nanomedicines.

Source: Journal of Nanobiotechnology

DOI: 10.1186/s12951-025-03850-9