Housley, S. N. | Search bioRxiv

bioRxiv2024

Tumor Agnostic Drug Delivery with Self-Agglomerating Nanohydrogels (SANGs)

RNA interference (RNAi) holds unique potential as a clinically viable modality to pharmacologically regulate oncogenes in sequence-specific manner. Despite its potential, systemic delivery of RNAi to tumors encounters myriad obstructions and strategies to overcome barriers have largely consisted of academic demonstrations, with few approaches reaching patients. Here, we report the development of a self-agglomerating nanohydrogel (SANGs) platform that is efficiently internalized by cancer cells, is agnostic to RNAi payload, and achieves functional suppression of multiple oncogene targets. After intravenous injection, SANGs preferentially accumulated and were retained ubiquitously in primary and metastatic loci in three aggressive cancer models in a species-agnostic manner. SANGs efficiently delivered multiple RNAi payloads that significantly suppressed oncogene expression and sensitized previously resistance tumors in vivo. SANGs were found to be safe and well tolerated in simulated clinical applications across three species. We then propose and verify a novel emergent mechanism by which SANGs achieve durable solid-tumor delivery without direct functionalization. Overall, our SANGs platform is an enabling technology for RNAi-based cancer therapeutics and is poised for advanced pharmaceutical development with multiple solid-tumor indications. One-Sentence SummaryOur nanostructure achieves safe and durable tumor-agnostic delivery through a newly described environmentally-responsive mechanism.

cancer biology↗

bioRxiv2019

Diverse muscle spindle firing properties emerge from multiscale muscle mechanics

AO_SCPLOWBSTRACTC_SCPLOWDespite decades of research, we lack a mechanistic framework capable of predicting how movement-related signals are transformed into the diversity of muscle spindle afferent firing patterns observed experimentally, particularly in naturalistic behaviors. Here, a biophysical model demonstrates that well-known firing characteristics of muscle spindle Ia afferents - including dependence on movement history, and nonlinear scaling with muscle stretch velocity - emerge from first principles of muscle contractile mechanics. Further, mechanical interactions of the muscle spindle with muscle-tendon dynamics reveal how motor commands to the muscle (alpha drive) versus muscle spindle (gamma drive) can cause highly variable and complex activity during active muscle contraction and muscle stretch that defy simple explanation. Depending on the neuromechanical conditions, the muscle spindle model output appears to "encode" aspects of muscle force, yank, length, stiffness, velocity, and/or acceleration, providing an extendable, multiscale, biophysical framework for understanding and predicting proprioceptive sensory signals in health and disease.

neuroscience↗