Non-viral Gene Delivery Methods for Bone and Joints

Viral carrier transport efficiency of gene delivery is high, depending on the
type of vector. However, viral delivery poses significant safety concerns such as
inefficient/unpredictable reprogramming outcomes, genomic integration, as well as
unwarranted immune responses and toxicity. Thus, non-viral gene delivery methods
are more feasible for translation as these allow safer delivery of genes and can
modulate gene expression transiently both in vivo, ex vivo, and in vitro. Based on
current studies, the efficiency of these technologies appears to be more limited, but
they are appealing for clinical translation. This review presents a summary of recent
advancements in orthopedics, where primarily bone and joints from the musculoskeletal
apparatus were targeted. In connective tissues, which are known to have a poor
healing capacity, and have a relatively low cell-density, i.e., articular cartilage, bone,
and the intervertebral disk (IVD) several approaches have recently been undertaken. We
provide a brief overview of the existing technologies, using nano-spheres/engineered
vesicles, lipofection, and in vivo electroporation. Here, delivery for microRNA (miRNA),
and silencing RNA (siRNA) and DNA plasmids will be discussed. Recent studies will
be summarized that aimed to improve regeneration of these tissues, involving the
delivery of bone morphogenic proteins (BMPs), such as BMP2 for improvement of bone
healing. For articular cartilage/osteochondral junction, non-viral methods concentrate on
targeted delivery to chondrocytes or MSCs for tissue engineering-based approaches.
For the IVD, growth factors such as GDF5 or GDF6 or developmental transcription
factors such as Brachyury or FOXF1 seem to be of high clinical interest. However, the
most efficient method of gene transfer is still elusive, as several preclinical studies have
reported many different non-viral methods and clinical translation of these techniques
still needs to be validated. Here we discuss the non-viral methods applied for bone and
joint and propose methods that can be promising in clinical use.