Photoswitchable Microgels for Dynamic Macrophage Modulation.

Dynamic manipulation of supramolecular self-assembled structures is achieved irreversibly or under non-physiological conditions, thereby limiting their biomedical, environmental, and catalysis applicability. In this study, microgels composed of azobenzene derivatives stacked via π-cation and π-π interactions are developed that are electrostatically stabilized with Arg-Gly-Asp (RGD)-bearing anionic polymers. Lateral swelling of RGD-bearing microgels occurs via cis-azobenzene formation mediated by near-infrared-light-upconverted ultraviolet light, which disrupts intermolecular interactions on the visible-light-absorbing upconversion-nanoparticle-coated materials. Real-time imaging and molecular dynamics simulations demonstrate the deswelling of RGD-bearing microgels via visible-light-mediated trans-azobenzene formation. Near-infrared light can induce in situ swelling of RGD-bearing microgels to increase RGD availability and trigger release of loaded interleukin-4, which facilitates the adhesion structure assembly linked with pro-regenerative polarization of host macrophages. In contrast, visible light can induce deswelling of RGD-bearing microgels to decrease RGD availability that suppresses macrophage adhesion that yields pro-inflammatory polarization. These microgels exhibit high stability and non-toxicity. Versatile use of ligands and protein delivery can offer cytocompatible and photoswitchable manipulability of diverse host cells.

pH-responsive biodegradable assemblies containing tunable phenyl-substituted vinyl ethers for use as efficient gene delivery vehicles.

Novel pH-responsive assemblies (PEG-lipid:DOPE liposomes) containing tunable and bifunctional phenyl-substituted vinyl ether (PIVE) cross-linkers were prepared. The assemblies consisted of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), acid-cleavable poly(ethylene glycol) (PEG)-conjugated lipids, pDNA, and protamine sulfate (PS). The PIVE linkage was designed to hydrolyze under acidic conditions, and the hydrolysis studies of PEG-lipid compounds containing PIVE at pH 4.2, 5.4, and 7.4 indicated that the hydrolysis rates of PIVE linker were influenced by the substitution of electron withdrawing or electron donating groups on the phenyl ring. Acid-catalyzed hydrolysis of PIVE leads to destabilization of the acid labile PEG-PIVE-lipid:DOPE liposomes via dePEGylation, thereby triggering content release. Content release assays showed that dePEGylation was highly pH-dependent and correlated with the PIVE proton affinity of the phenyl group. These results indicated that the dePEGylative triggering based on a new pH-sensitive PIVE linkage can be controlled. In vitro transfection studies on the pH-responsive assemblies containing mPEG-(MeO-PIVE)-conjugated 1,3-dioctadecyl-rac-glycerol lipids (mPEG-(MeO-PIVE])-DOG) showed higher transfection efficiency compared to that of polyethylenimine (PEI), a positive control, on HEK 293 and COS-7 cells. In addition, lower cytotoxicity of PEG-PIVE-lipid:DOPE liposomes/PS/DNA was observed in comparison to PEI. These results suggest that PEG-PIVE-lipid:DOPE liposomes can be considered as nonviral vehicles for drug and gene delivery applications.