Biodegradable lipophilic polymeric mRNA nanoparticles for ligand-free targeting of splenic dendritic cells for cancer vaccination.

Nanoparticle (NP)-based mRNA cancer vaccines hold great promise to realize personalized cancer treatments. To advance this technology requires delivery formulations for efficient intracellular delivery to antigen-presenting cells. We developed a class of bioreducible lipophilic poly(beta-amino ester) nanocarriers with quadpolymer architecture. The platform is agnostic to the mRNA sequence, with one-step self-assembly allowing for delivery of multiple antigen-encoding mRNAs as well as codelivery of nucleic acid-based adjuvants. We examined structure-function relationships for NP-mediated mRNA delivery to dendritic cells (DCs) and identified that a lipid subunit of the polymer structure was critical. Following intravenous administration, the engineered NP design facilitated targeted delivery to the spleen and preferential transfection of DCs without the need for surface functionalization with targeting ligands. Treatment with engineered NPs codelivering antigen-encoding mRNA and toll-like receptor agonist adjuvants led to robust antigen-specific CD8+ T cell responses, resulting in efficient antitumor therapy in in vivo models of murine melanoma and colon adenocarcinoma.

Approach to chronic wrist pain in adults: Review of common pathologies for primary care practitioners.

OBJECTIVE: To develop an approach for identifying, investigating, and initially managing common causes of chronic wrist pain seen by primary care practitioners. SOURCES OF INFORMATION: Relevant clinical evidence and literature were identified using the PubMed database. MAIN MESSAGE: Chronic wrist pain is a common presentation in the primary care setting. The complex anatomy of the wrist leads to a broad differential diagnosis. Elements of history, findings of physical examinations and investigations, and management relevant to the following pathologies are discussed, including scaphoid fracture nonunion, thumb carpometacarpal joint osteoarthritis, scapholunate ligament instability, triangular fibrocartilage complex injuries, de Quervain tenosynovitis, extensor carpi ulnaris tendinopathy, carpal tunnel syndrome, and ganglion cysts. When evaluating chronic wrist pain, diagnostic imaging with x-ray scans can serve as an important ancillary investigation tool but should not override clinical suspicion. Advanced imaging (computed tomography or magnetic resonance imaging) is generally best ordered by a hand surgeon when it will help clarify a diagnosis and guide treatment. CONCLUSION: Chronic wrist pain is a functionally limiting problem best managed with timely diagnosis and treatment. A thorough history and physical examination are the cornerstones of an effective evaluation. When diagnosis is delayed, some wrist pathologies can lead to relatively poor outcomes, such as a scaphoid fracture nonunion resulting in diffuse wrist osteoarthritis.

Photocrosslinked Bioreducible Polymeric Nanoparticles for Enhanced Systemic siRNA Delivery as Cancer Therapy.

Clinical translation of polymer-based nanocarriers for systemic delivery of RNA has been limited due to poor colloidal stability in the blood stream and intracellular delivery of the RNA to the cytosol. To address these limitations, this study reports a new strategy incorporating photocrosslinking of bioreducible nanoparticles for improved stability extracellularly and rapid release of RNA intracellularly. In this design, the polymeric nanocarriers contain ester bonds for hydrolytic degradation and disulfide bonds for environmentally triggered small interfering RNA (siRNA) release in the cytosol. These photocrosslinked bioreducible nanoparticles (XbNPs) have a shielded surface charge, reduced adsorption of serum proteins, and enable superior siRNA-mediated knockdown in both glioma and melanoma cells in high-serum conditions compared to non-crosslinked formulations. Mechanistically, XbNPs promote cellular uptake and the presence of secondary and tertiary amines enables efficient endosomal escape. Following systemic administration, XbNPs facilitate targeting of cancer cells and tissue-mediated siRNA delivery beyond the liver, unlike conventional nanoparticle-based delivery. These attributes of XbNPs facilitate robust siRNA-mediated knockdown in vivo in melanoma tumors colonized in the lungs following systemic administration. Thus, biodegradable polymeric nanoparticles, via photocrosslinking, demonstrate extended colloidal stability and efficient delivery of RNA therapeutics under physiological conditions, and thereby potentially advance systemic delivery technologies for nucleic acid-based therapeutics.