Alessio Malfanti

The prognosis for glioblastoma patients remains poor despite recent advances in neurosurgery, chemotherapy, and radiotherapy. One promising treatment strategy lies in the localized delivery of therapeutics through drug delivery systems designed to enhance existing clinical treatments by directly targeting the tumor site or surrounding area. This review explores the latest advancements in localized therapies for glioblastoma, highlighting recent preclinical and clinical studies and examining how we can integrate these approaches - including stereotactic techniques such as convection-enhanced delivery and therapies targeting the post-surgical resection cavity - with drug delivery systems. We describe the features that the drug delivery system should possess for the efficient transport of drugs for both inoperable and resectable glioblastoma local treatment. Finally, this review discusses future directions that may facilitate the clinical translation of localized treatment strategies for glioblastoma.

Nanomedicines offer a means to overcome the limitations associated with traditional drug dosage formulations by affording drug protection, enhanced drug bioavailability, and targeted drug delivery to affected sites. Inflamed tissues possess unique microenvironmental characteristics (including excessive reactive oxygen species, low pH levels, and hypoxia) that stimuli-responsive nanoparticles can employ as triggers to support on-demand delivery, enhanced accumulation, controlled release, and activation of anti-inflammatory drugs. Stimuli-responsive nanomedicines respond to physicochemical and pathological factors associated with diseased tissues to improve the specificity of drug delivery, overcome multidrug resistance, ensure accurate diagnosis and precision therapy, and control drug release to improve efficacy and safety. Current stimuli-responsive nanoparticles react to intracellular/microenvironmental stimuli such as pH, redox, hypoxia, or specific enzymes and exogenous stimuli such as temperature, magnetic fields, light, and ultrasound via bioresponsive moieties. This review summarizes the general strategies employed to produce stimuli-responsive nanoparticles tailored for inflammatory diseases and all recent advances, reports their applications in drug delivery, and illustrates the progress made toward clinical translation.

Harnessing the effect of the cyclic GMP-AMP Synthase-STimulator of INterferon Genes (cGAS-STING) signaling pathway has emerged as a promising approach to developing novel strategies for the oral treatment of inflammatory bowel disease (IBD). In this work, we screened different cGAS-STING inhibitors in vitro in murine macrophages. Then, we encapsulated the cGAS-STING inhibitor H-151 within lipid nanocapsules (LNCs), owing to their inherent ability to induce the secretion of glucagon-like peptide 2 (GLP-2), a re-epithelizing peptide, upon oral administration. We demonstrated that our formulation (LNC(H-151)) could induce GLP-2 secretion and selectively target the cGAS-STING pathway and its downstream key markers (including TBK1 and pTBK1) while reducing the expression of pro-inflammatory cytokines associated with the cGAS-STING pathway (TNF-α and CXCL10) in murine macrophages. In an in vivo acute dextran sodium sulfate (DSS)-induced colitis mouse model, the oral administration of LNC(H-151) significantly reduced pro-inflammatory cytokines to levels comparable to the CTRL Healthy group while promoting mucosal healing. The therapeutic potential of this scalable and cost-effective nanomedicine warrants further investigation as an alternative for the oral treatment of IBD.

Current treatments for inflammatory bowel disease (IBD) treatment consist of anti-inflammatory products. In this study, we sought to induce the physiological secretion of glucagon-like peptide 2, a peptide with intestinal growth-promoting activity, via nanoparticles while simultaneously providing with immunomodulation by tailoring the nanoparticle surface. To this end, we developed hybrid lipid hyaluronate-KPV conjugated nanoparticles loaded with teduglutide for combination therapy in IBD. The nanocarriers induced (or did not induce) immunosuppression depending on the presence (or absence) of a hyaluronan-KPV functionalization. This strategy holds promise as a nanoparticle platform for combined mucosal healing and immunomodulation in IBD treatment.