Dual ligands synergistically driven direct penetration of nanoparticles: insights from computational simulations

Direct penetration of nanoparticles, acting as a main transmembrane delivery pathway, has attracted considerable research interest in the field of drug delivery due to its high delivery efficiency and minimal drug degradation. Herein, using dissipative particle dynamics simulations, the direct penetration processes of dual-ligand decorated nanoparticles have been systematically studied to optimize the decoration strategies of two types of ligands, thereby enhancing the direct transmembrane delivery capacities. The simulation results indicate that the physicochemical properties of dual ligands decorated on nanoparticle surfaces synergistically govern the transmembrane delivery pathway. By quantitatively analyzing the relationship between delivery pathways and the physicochemical properties of dual ligands, including the decoration pattern, the specific ligand ratio, the specific interaction strength, the protonation degree of the non-specific ligands, and the initial orientation angle, the dependence of direct penetration on multiple factors has been revealed. The established direct penetration mechanism indicates that the direct penetration of nanoparticles is achieved through the synergistic contributions of non-specific and specific ligands: the former drive nanoparticle insertion into membranes, while the latter drive internalization into the interior of tumor cells. More importantly, the restrictive effects imposed by the respective opposing ligands on both the insertion and the internalization stages are also clarified. Accordingly, an optimized dual-ligand decoration strategy is proposed, enabling a direct penetration probability exceeding 93%. Furthermore, the final phase diagrams are also constructed to serve as a design guideline for realizing direct penetration of dual-ligand decorated nanoparticles. These simulation results provide significant insights into the rational design of dual-ligand decoration on nanoparticle surfaces to achieve efficient direct penetration, thereby offering valuable guidance for the development of nanocarrier delivery systems in biomedical applications.