Rekindling RNAi Therapy: Materials Design Requirements for In Vivo siRNA Delivery

With the recent FDA approval of the first siRNA‐derived therapeutic, RNA interference (RNAi)‐mediated gene therapy is undergoing a transition from research to the clinical space. The primary obstacle to realization of RNAi therapy has been the delivery of oligonucleotide payloads. Therefore, the main aims is to identify and describe key design features needed for nanoscale vehicles to achieve effective delivery of siRNA‐mediated gene silencing agents in vivo. The problem is broken into three elements: 1) protection of siRNA from degradation and clearance; 2) selective homing to target cell types; and 3) cytoplasmic release of the siRNA payload by escaping or bypassing endocytic uptake. The in vitro and in vivo gene silencing efficiency values that have been reported in publications over the past decade are quantitatively summarized by material type (lipid, polymer, metal, mesoporous silica, and porous silicon), and the overall trends in research publication and in clinical translation are discussed to reflect on the direction of the RNAi therapeutics field.     

Nanoparticles for Gene Delivery

Nanocarriers are a new type of nonviral gene carriers, many of which have demonstrated a broad range of pharmacological and biological properties, such as being biodegradable in the body, stimulus‐responsive towards the surrounding environment, and an abiltiy to specifically targeting certain disease sites. By summarizing some main types of nanocarriers, this Concept considers the current status and possible future directions of the potential clinical applications of multifunctional nanocarriers, with primary attention on the combination of such properties as biodegradability, targetability, transfection ability, and stimuli sensitivity.     

Detection of Circulating Cancer Cells Using Electrocatalytic Gold Nanoparticles

A rapid cancer cell detection and quantification assay, based on the electrocatalytic properties of gold nanoparticles towards the hydrogen evolution reaction, is described. The selective labeling of cancer cells is performed in suspension, allowing a fast interaction between the gold nanoparticle labels and the target proteins expressed at the cell membrane. The subsequent electrochemical detection is accomplished with small volumes of sample and user‐friendly equipment through a simple electrochemical method that generates a fast electrochemical response used for the quantification of nanoparticle‐labeled cancer cells. The system establishes a selective cell‐detection assay capable of detecting 4 × 10³ cancer cells in suspension that can be extended to several other cells detection scenarios.     

Near‐Infrared‐Resonant Gold/Gold Sulfide Nanoparticles as a Photothermal Cancer Therapeutic Agent

The development and optimization of near‐infrared (NIR)‐absorbing nanoparticles for use as photothermal cancer therapeutic agents has been ongoing. This work exploits the properties of gold/gold sulfide NIR‐absorbing nanoparticles (≈35–55 nm) that provide higher absorption (98% absorption and 2% scattering for gold/gold sulfide versus 70% absorption and 30% scattering for gold/silica nanoshells) as well as potentially better tumor penetration. The ability to ablate tumor cells in vitro and efficacy for photothermal cancer therapy is demonstrated, and an in vivo model shows significantly increased long‐term, tumor‐free survival. Furthermore, enhanced circulation and biodistribution is observed in vivo. This class of NIR‐absorbing nanoparticles has the potential to improve upon photothermal tumor ablation for cancer therapy.     

Superparamagnetic Gold Nanoparticles Synthesized on Protein Particle Scaffolds for Cancer Theragnosis

Cancer theragnosis using a single multimodality agent is the next mainstay of modern cancer diagnosis, treatment, and management, but a clinically feasible agent with in vivo cancer targeting and theragnostic efficacy has not yet been developed. A new type of cancer theragnostic agent is reported, based on gold magnetism that is induced on a cancer‐targeting protein particle carrier. Superparamagnetic gold‐nanoparticle clusters (named SPAuNCs) are synthesized on a viral capsid particle that is engineered to present peptide ligands targeting a tumor cell receptor (TCR). The potent multimodality of the SPAuNCs is observed, which enables TCR‐specific targeting, T₂‐weighted magnetic resonance imaging, and magnetic hyperthermia therapy of both subcutaneous and deep‐tissue tumors in live mice under an alternating magnetic field. Furthermore, it is analytically elucidated how the magnetism of the SPAuNCs is sufficiently induced between localized and delocalized spins of Au atoms. In particular, the SPAuNCs show excellent biocompatibility without the problem of in vivo accumulation and holds promising potential as a clinically effective agent for cancer theragnosis.     

Cancer-Targeting Nanoparticles for Combinatorial Nucleic Acid Delivery

Nucleic acids are a promising type of therapeutic for the treatment of a wide range of conditions, including cancer, but they also pose many delivery challenges. For efficient and safe delivery to cancer cells, nucleic acids must generally be packaged into a vehicle, such as a nanoparticle, that will allow them to be taken up by the target cells and then released in the appropriate cellular compartment to function. As with other types of therapeutics, delivery vehicles for nucleic acids must also be designed to avoid unwanted side effects; thus, the ability of such carriers to target their cargo to cancer cells is crucial. Classes of nucleic acids, hurdles that must be overcome for effective intracellular delivery, types of nonviral nanomaterials used as delivery vehicles, and the different strategies that can be employed to target nucleic acid delivery specifically to tumor cells are discussed. Additonally, nanoparticle designs that facilitate multiplexed delivery of combinations of nucleic acids are reviewed.     

Cationic Bovine Serum Albumin Based Self‐Assembled Nanoparticles as siRNA Delivery Vector for Treating Lung Metastatic Cancer

It is generally believed that intravenous application of cationic vectors is limited by the binding of abundant negatively charged serum components, which may cause rapid clearance of the therapeutic agent from the blood stream. However, previous studies show that systemic delivery of cationic gene vectors mediates specific and efficient transfection within the lung, mainly as a result of interaction of the vectors with serum proteins. Based on these findings, a novel and charge‐density‐controllable siRNA delivery system is developed to treat lung metastatic cancer by using cationic bovine serum albumin (CBSA) as the gene vector. By surface modification of BSA, CBSA with different isoelectric points (pI) is synthesized and the optimal cationization degree of CBSA is determined by considering the siRNA binding and delivery ability, as well as toxicity. The CBSA can form stable nanosized particles with siRNA and protect siRNA from degradation. CBSA also shows excellent abiliies to intracellularly deliver siRNA and mediate significant accumulation in the lung. When Bcl2‐specific siRNA is introduced to this system, CBSA/siRNA nanoparticles exhibit an efficient gene‐silencing effect that induces notable cancer cell apoptosis and subsequently inhibits the tumor growth in a B16 lung metastasis model. These results indicate that CBSA‐based self‐assembled nanoparticles can be a promising strategy for a siRNA delivery system for lung targeting and metastatic cancer therapy.