Precision medicine for chronic neuropathic pain: A multiplatform approach to drug delivery

Chronic neuropathic pain (CNP) arises from lesions or diseases of the somatosensory nervous system and poses a complex pathophysiological challenge, often involving neuroinflammatory processes and aberrant neuronal signaling. Clinically, CNP affects a significant population worldwide and is notoriously difficult to manage with current treatments. Standard pharmacological therapies including gabapentinoids and antidepressants as first-line agents, and opioids as second-line frequently provide only partial relief and carry serious limitations. Opioids, in particular, are associated with adverse effects, risk of tolerance/addiction, and other complications, which restrict their long-term utility. These shortcomings underscore an urgent need for innovative, targeted, and less toxic analgesic solutions. In this context, biomaterial or nanotechnology-driven precision medicine has emerged as a promising strategy to achieve effective pain control while minimizing systemic side effects. This PhD thesis addresses the need for better CNP therapies by developing advanced drug delivery systems through a multiplatform precision nanomedicine approach. Four complementary strategies were studied. First, microRNA-based delivery systems were explored to modulate pain-related molecular pathways in the dorsal root ganglia (DRG), capitalizing on the role of dysregulated miRNAs in neuropathic pain signaling. Second, a thermo-responsive injectable hydrogel was formulated for sustained local release of lidocaine and crobenetine (a sodium channel blockers), creating an in-situ drug depot that prolongs analgesia at the affected site. Third, polymeric nanoparticles were engineered by blending polyethylene glycol (PEG) with poly (lactic-co-glycolic acid) (PLGA) and compared to conventional PLGA nanoparticles for the controlled delivery of sodium channel blockers, to evaluate how PEG incorporation influences drug release kinetics and biocompatibility. Fourth, novel PEG–lipid conjugates were synthesized for integration into poly(2- (dimethylamino)ethyl methacrylate) (pDMAEMA)-based polymers to enhance their gene transfection efficiency, aiming to improve the non-viral delivery of therapeutic genes to pain- modulating cells. Each of these platforms was rigorously characterized using a broad suite of techniques. Swelling analysis and gelation kinetics measurements were employed for the hydrogel systems, ensuring optimal injectability and thermal gelling behavior. Drug encapsulation efficiency and release profiling (including in vitro release studies under simulated inflammatory conditions) were conducted to validate controlled delivery performance. Scanning electron microscopy (SEM) provided insights into nanoparticle size and morphology, while dynamic light scattering (DLS) was used to determine particle size distributions and zeta potential for nanoparticle stability. Fourier-transform infrared spectroscopy (FTIR) confirmed the chemical composition and successful conjugation and encapsulation in polymer-based carriers. Collectively, the outcomes of this work demonstrate a precision medicine paradigm for CNP treatment, wherein multiple nanotechnology platforms are tailored to target the condition’s multifaceted pathophysiology while reducing systemic toxicity. This thesis contributes to the advancement of targeted, long-acting neuropathic pain therapies and underscores their clinical relevance. Importantly, it highlights the future potential of combining such nanomedicine platforms to achieve synergistic improvements in therapeutic efficacy and safety for patients suffering from chronic neuropathic pain.