Gemini lipid interfaces confer enhanced pH responsiveness and hemocompatibility on surface-engineered nanocrystals

Engineering compact, stimuli-responsive interfaces on nanocrystals is critical for advancing their biomedical utility. Here, we report gemini N-palmitoyl homocysteine (GPHC) lipid-capped CuInZnS₂ (CIZS) nanocrystals that exhibit reversible pH-responsive fluorescence, enhanced photostability, and superior hemocompatibility compared to PEGylated counterparts. The dual-head, dual-tail architecture enables dense surface packing and dynamic protonation-dependent reorganization, allowing reversible assembly-disassembly and sustained emission across physiological (pH 7.4) to acidic tumor (pH ≈ 5-6) environments. GPHC-CIZS nanocrystals retain >90% emission under prolonged irradiation and show minimal fluorescence loss under acidic conditions, unlike PEGylated systems. Biological studies reveal improved cytocompatibility, reduced hemolysis, and stable coagulation parameters. Notably, these nanocrystals exhibit tumor-selective uptake and prolonged intratumoral retention, driven by pH-dependent aggregation behavior. In vivo biodistribution and biochemical analyses confirm minimal systemic toxicity. Collectively, this work establishes gemini lipid interfaces as a compact, adaptive alternative to PEGylation, enabling environmentally responsive, biocompatible nanocrystals for imaging and diagnostic applications.