The Human Genome Project continues to reveal the genetic basis for numerous acquired and inherited diseases ranging from cancer, HIV, and heart disease to muscular dystrophy and hemophilia. With this wealth of information, the ability to design patient-specific drugs that alter the cellular machinery at the genetic level in a way that controls or treats a specific disease will increasingly become a reality. Designing nucleic acid drugs as well as engineering novel delivery vehicles that encapsulate and effectively transport genetic materials into cells provides an opportunity to enhance the understanding of disease mechanisms and may help treat or cure these diseases. This issue of MRS Bulletin on “Designer Materials for Nucleic Acid Delivery” explores the diverse materials—polymers, lipids, nanoparticles, biocompatible scaffolds, and engineered peptides—that are being evaluated for the intracellular delivery of nucleic acids. These synthetic delivery systems are actively being investigated for many research purposes that range from gene-based therapy, genetic vaccine, and RNA interference to gene function and cellular signaling studies. This area is currently being pursued by a broad group of academic, clinical, and industrial researchers at both the fundamental and applied level, motivated by the widespread implications for human health. In this introductory article, we provide a general tutorial to gene-based therapies and a brief overview of the many areas of materials research that are currently making a tremendous impact on this interdisciplinary field.We conclude with a discussion of the future challenges that materials researchers face in developing viable nucleic acid delivery vehicles.

Gene therapy harbors great promise for the treatment of a variety of inherited and acquired diseases, but its potential can be realized only with safe and effective carriers. Although viruses can efficiently transfer foreign genes to cells, their long-term safety remains a concern. Polymers can serve as a carrier to facilitate gene transfer, either by condensing DNA to the size of nanoparticles that can be internalized by cells, or by entrapping DNA in matrices or micro/nanoparticles for sustained release. However, polymeric controlled gene delivery remains highly inefficient. This review covers the major barriers for nonviral gene transfer and briefly describes the different types of polymers developed to overcome these barriers. With the tremendous promise of genetic medicine, nonviral gene delivery is a worthy goal for biomaterials and nanotechnology research.

The design of safe and efficient gene transfer vectors remains one of the key challenges in gene therapy. Despite their remarkable transfection efficiency, viral vectors suffer from known safety issues. Consequently, significant research activity has been undertaken to develop nonviral approaches to gene transfer during the last decade. Numerous academic and industrial research groups are investigating synthetic cationic vectors, such as cationic amphiphiles, with the objective of increasing the gene transfection activity. Within this area, the development of functional synthetic vectors that respond to local environmental effects have met with success. These synthetic vectors are based on mechanistic principles and represent a significant departure from earlier systems. Many of these systems for gene delivery in vitro and in vivo are discussed in this article.

Nonviral DNA delivery systems have great therapeutic and prophylactic potential, but their clinical utility has been limited by three major barriers: (1) inefficient uptake by the cell, (2) insufficient release of DNA within the cell, and (3) ineffective nuclear targeting and transport. Since the size of most cells is in the micrometer regime and the space inside a cell is extremely crowded, ideal DNA delivery systems must be in the nanometer range. Advancements in nanoscale science and nanotechnology have provided us with novel nanoparticles that may overcome all of these barriers, leading to higher-efficiency DNA delivery. This review article will focus on the recent developments in nanoscale DNA delivery systems that consist of chemical dendrimers, DNA dendrimers, nanospheres, nanolayers, nanorods, and nanotubes. The future of DNA delivery systems that interface with nanotechnology is also discussed.

Biomaterials can potentially enhance the delivery of viral and nonviral vectors for both basic science and clinical applications.Vectors typically consist of nucleic acids (DNA, RNA) packaged with proteins, lipids, or cationic polymers, which facilitate cellular internalization and trafficking. These vectors can associate with biomaterials that support cell adhesion, a process we term substrate-mediated delivery. Substrate immobilization localizes the DNA and the delivery vector to the cellular microenvironment.The interaction between the vector and substrate must be appropriately balanced to mediate immobilization, yet allow for cellular internalization. Balancing the binding between the biomaterial and the vector is dependent upon the surface chemistries of the material and the vector, which can be designed to provide both specific (e.g., biotin–avidin, the strongest known noncovalent interaction between a protein and its ligand) and nonspecific (e.g., van der Waals) interactions. In this review, we describe the biomaterial and vector properties that mediate binding and gene transfer, identify potential applications, and present opportunities for further development.

Numerous barriers, both extracellular and intracellular, hinder successful and efficient nonviral nucleic acid delivery. Due to their small size and ability to specifically recognize and interact with molecular targets, peptides can be incorporated as modular elements into synthetic nucleic acid delivery systems to overcome many of these barriers. Three classes of peptides that have frequently been integrated as components in nucleic acid delivery systems include cell-penetrating peptides (CPPs), endosomal release peptides, and nuclear localization sequences (NLSs).Various additional classes of peptides show promise for enhancing nucleic acid delivery by targeting cell surface receptors, inhibiting nuclease activity, and directing nucleic acids toward intracellular targets. In addition to a review of the various existing approaches to peptide-enhanced nucleic acid delivery, this article will discuss strategies for the development of new peptides and approaches for the incorporation of these peptides into nucleic acid delivery systems.