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.

Liposomes have been one of the most exploited drug delivery systems in recent decades. However, their large-scale production with low batch-to-batch differences is a challenge for industry, which ultimately delays the clinical translation of new products. We have investigated the effects of formulation parameters on the colloidal and biopharmaceutical properties of liposomes generated with a thin-film hydration approach and microfluidic procedure. Dexamethasone hemisuccinate was remotely loaded into liposomes using a calcium acetate gradient. The liposomes produced by microfluidic techniques showed a unilamellar structure, while the liposomes produced by thin-film hydration were multilamellar. Under the same remote loading conditions, a higher loading capacity and efficiency were observed for the liposomes obtained by microfluidics, with low batch-to-batch differences. Both formulations released the drug for almost one month with the liposomes prepared by microfluidics showing a slightly higher drug release in the first two days. This behavior was ascribed to the different structure of the two liposome formulations. In vitro studies showed that both formulations are non-toxic, associate to human Adult Retinal Pigment Epithelial cell line-19 (ARPE-19) cells, and efficiently reduce inflammation, with the liposomes obtained by the microfluidic technique slightly outperforming. The results demonstrated that the microfluidic technique offers advantages to generate liposomal formulations for drug-controlled release with an enhanced biopharmaceutical profile and with scalability.

Well-defined synthetic branched nanostructures form an emerging subclass of macromolecular structures whose 3D structure and multivalency offer unique opportunities for fine-tuning internalization and cellular targeting. Dendrimers possess a well-defined 3D-globular backbone with highly versatile functional surface groups and exhibit a range of chemical and biological properties. Branched polymers present unique opportunities for the targeted delivery of diverse bioactive molecules (including targeting ligands, imaging probes, and drugs) via conjugation to multiple sites within the structure. The inherent versatility and multifunctionality of these architectures make them potentially useful for the modulation of multiple immune-related pathways for the treatment of a wide range of diseases and disorders, including cancer and human immunodeficiency virus infection. Herein, we describe the key components of the immune system whose targeting can help overcome immune-related disorders and discuss branched polymers (including dendrimers) as promising delivery systems with unique immunomodulatory properties against cancer and infectious diseases.

Glioblastoma is an unmet clinical need. Local treatment strategies offer advantages, such as the possibility to bypass the blood–brain barrier, achieving high drug concentrations at the glioblastoma site, and consequently reducing systemic toxicity. In this study, we evaluated the feasibility of using hyaluronic acid (HA) for the local treatment of glioblastoma. HA was conjugated to doxorubicin (DOX) with distinct bio-responsive linkers (direct amide conjugation HA-NH-DOX), direct hydrazone conjugation (HA-Hz-DOX), and adipic hydrazone (HA-AdpHz-DOX). All HA-DOX conjugates displayed a small size (less than 30 nm), suitable for brain diffusion. HA-Hz-DOX showed the best performance in killing GBM cells in both 2D and 3D in vitro models and displayed superior activity in a subcutaneous GL261 tumor model in vivo compared to free DOX and other HA-DOX conjugates. Altogether, these results demonstrate the feasibility of HA as a polymeric platform for the local treatment of glioblastoma and the importance of rationally designing conjugates.