ARTICLES nature materials | VOL 3 | AUGUST 2004 | www.nature.com/naturematerials 569 B iological mineralization and demineralization play a vital role in our life and the environment around us. The process of biomineralization has inspired the development of approaches for creating new materials for intracellular or extracellular manipulation. Recent advances involve patterning minerals onto microstructured surfaces for more biocompatible bone implants 1 , incorporating minerals into a biodegradable matrix for guided tissue regeneration 2,3 , and absorption of protein or drug onto porous minerals for local delivery 4 . These approaches either used an organic or inorganic matrix (silicon, synthetic polymers, proteins and other macromolecules) as a framework for growth of the inorganic structure, or used formed minerals as a structural support. We reasoned that if macromolecules (DNA, protein, peptides, oligonucleotides) could be co-deposited on a cell-culture surface with inorganic minerals in the process of biomineralization, they might form bioactive nanocomposites in which the functional macromolecule is concentrated in close proximity to the cell. Further, if the structure of the nanocomposites and release of macromolecules from the nanocomposites could be regulated, these factors might be used to control delivery of macromolecules into the cell. The challenge of a gene-transfer system is to direct DNA—a large molecule of over 1 million dalton having a high negative charge—into cells and intracellular compartments for gene expression. This is usually accomplished by adding DNA/material complexes into the solution bathing the cell. Cationic polymers 5–7 , lipids 8–10 or calcium phosphates 11,12 are currently used to form nano- or microscale complexes with DNA for facilitating gene transfer. But these systems have several drawbacks including poor control of the size of complex, and inefficiency or toxicity when maintaining high DNA concentration near the cell surface. It has been suggested that DNA transfer can be enhanced by creating regions of high DNA concentration in the microenvironment of cells 7,13 . Therefore, we tested the hypothesis that a system that provided control over nanocomplex formation, and that placed these complexes on a surface in close proximity to the cells,would provide enhanced gene transfer. The aim of this study was to examine the formation DNA/calcium phosphate nanocomposites on a surface suitable for cell culture, Safe and efficient gene delivery would have great potential in gene therapy and tissue engineering, but synthetic biomaterial surfaces endowed with efficient gene- transferring functions do not yet exist. Inspired by naturally occurring biomineralization processes, we co-precipitated DNA with inorganic minerals onto cell-culture surfaces. The DNA/mineral nanocomposite surfaces obtained not only supported cell growth but also provided high concentrations of DNA in the immediate microenvironment of the cultured cells. Gene transfer from the engineered surfaces was as efficient as an optimized commercial lipid transfection reagent; in addition, the extent of gene transfer was adjustable by varying the mineral composition. DNA/mineral nanocomposite surfaces represent a promising system for enhancing gene transfer and controlling the extent of gene transfer for various biomedical applications, including tissue engineering or gene therapy of bone. Surface-mediated gene transfer from nanocomposites of controlled texture HONG SHEN 1 *, JIAN TAN 1 * AND W. MARK SALTZMAN 2† 1 School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York 14853, USA 2 Department of Biomedical Engineering, Yale University, New Haven, Connecticut 06520, USA *These authors contributed equally to the work † e-mail address: mark.saltzman@yale.edu Published online: 18 July 2004; doi:10.1038/nmat1179 ©2004 Nature Publishing Group