A Bioinspired Phytyl Tripod Anchor for Engineering Liposomal and Cellular Surfaces as a Robust Colloidal Delivery Platform

Inspired by the phytyl chains of chlorophylls and tocopherols, we developed a robust phytyl tripod anchor for cell surface engineering in this work. The anchor exhibited markedly stronger membrane anchoring than the widely used 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) anchor, as reflected by a lower critical micellization concentration (0.119 vs 0.189 mM) and a more negative Gibbs free energy of liposome binding (-29.85 vs -28.15 kJ/mol). Using this anchor, we established a liposome-relayed bioorthogonal manipulation platform that enables site-specific cell surface engineering in vivo. In a zebrafish inflammation model, liposomes decorated with amphiphilic hyaluronic acid (HA) first delivered the phytyl tripod anchor selectively to inflamed tissue, and subsequently injected clickable catalase and liposomal curcumin were then captured in situ via bioorthogonal click chemistry, anchoring them onto the target cell surface. This two-step strategy produced substantially enhanced therapeutic effects. We further extended the platform into a photothermal enhanced liposome delivery system. Clickable magnetic nanoparticles, synthesized via a PEGylated gallic acid approach, were bioorthogonally conjugated to cell membranes and liposomes through the phytyl tripod anchor. Curcumin was additionally derivatized with the endoplasmic reticulum (ER) targeting KKAA peptide to enable organelle-specific delivery. In an inflammation model with RAW264.7 cells, this photothermal-enhanced system significantly improved the anti-inflammatory efficacy. The developed phytyl tripod anchor and the derived bioorthogonal strategies hold great promise for precision cell surface engineering and targeted delivery of bioactives.