Spatio-temporal delivery of both intra- and extracellular toll-like receptor agonists for enhancing antigen-specific immune responses.

For cancer immunotherapy, triggering toll-like receptors (TLRs) in dendritic cells (DCs) can potentiate antigen-based immune responses. Nevertheless, to generate robust and long-lived immune responses, a well-designed nanovaccine should consider different locations of TLRs on DCs and co-deliver both antigens and TLR agonist combinations to synergistically induce optimal antitumor immunity. Herein, we fabricated lipid-polymer hybrid nanoparticles (LPNPs) to spatio-temporally deliver model antigen ovalbumin (OVA) on the surface of the lipid layer, TLR4 agonist monophosphoryl lipid A (MPLA) within the lipid layer, and TLR7 agonist imiquimod (IMQ) in the polymer core to synergistically activate DCs by both extra- and intra-cellular TLRs for enhancing adaptive immune responses. LPNPs-based nanovaccines exhibited a narrow size distribution at the mean diameter of 133.23 nm and zeta potential of -2.36 mV, showed a high OVA loading (around 70.83 µg/mg) and IMQ encapsulation efficiency (88.04%). Our data revealed that LPNPs-based nanovaccines showed great biocompatibility to immune cells and an excellent ability to enhance antigen internalization, thereby promoting DCs maturation and cytokines production. Compared to Free OVA, OVA-LPNPs promoted antigen uptake, lysosome escape, depot effect and migration to secondary lymphatic organs. In vivo immunization showed that IMQ-MPLA-OVA-LPNPs with dual agonists induced more powerful cellular and humoral immune responses. Moreover, prophylactic vaccination by IMQ-MPLA-OVA-LPNPs effectively suppressed tumor growth and increased survival efficacy. Hence, the nanovaccines we fabricated can effectively co-deliver antigens and different TLR agonists and realize coordinated stimulation of DCs in a spatio-temporal manner for enhanced immune responses, which provides a promising strategy for cancer immunotherapy.

Gas-generating mesoporous silica nanoparticles with rapid localized drug release for enhanced chemophotothermal tumor therapy.

Chemophotothermal combination therapy has emerged as a novel and promising strategy to treat cancer. To improve anticancer effectiveness and reduce systemic toxicity, it is essential to trigger drug release at tumor sites or within tumor cells for maximal drug exposure. Herein, we constructed gas-generating mesoporous silica nanoparticles (MSNs) that can load ammonium bicarbonate (ABC) and doxorubicin (DOX) within the pores, encapsulate indocyanine green (ICG) onto the polydopamine (PDA) layer, and modify the RGD peptide on the outer surface [denoted as M(abc)-DOX@PDA-ICG-PEG-RGD] for triggered drug release and targeted chemophotothermal combination therapy. Upon hyperthermia or low pH value, the encapsulated ABC can efficiently generate CO2 gas, thus enhancing the damage to the PDA layer and accelerating DOX release. In vitro experiments showed that the M(abc)-DOX@PDA-ICG-PEG-RGD significantly enhanced cellular uptake and cytotoxicity, and laser irradiation further increased the endocytic and cytotoxic effects. An in vivo study indicated that the nanoparticles can effectively accumulate at the tumor site and significantly inhibited tumor growth with no side-effects to the normal organs. Thus, this gas-generating MSN-based nanocarrier that can trigger drug release in response to laser irradiation or low pH value holds great potential in enhancing cancer chemophotothermal combination therapy.

The preparation of hyaluronic acid grafted pullulan polymers and their use in the formation of novel biocompatible wound healing film.

A series of hyaluronic acid grafted pullulan (HA-g-Pu) polymers with different hyaluronic acid (HA) moieties degrees of substitution (DS) were synthesized and characterized by fourier transform infrared (FT-IR), proton nuclear magnetic resonance (1H NMR) and differential scanning calorimetry measurement (DSC). Compared to pure HA, HA-g-Pu polymers obtained better anti-enzymatic degradation ability in vitro, and the degradation rate of HA-g-Pu polymers depended on their different DS of HA moieties. The HA-g-Pu films were made of leaf-shape cascading arrangement with many small porous ranging from 0 to 100 µm in diameter when observed by scanning electron microscopy (SEM). Therefore, HA-g-Pu films have a higher swelling ratio than that of the pullulan/or HA films. HA-g-Pu films could absorb much liquid, effectively protect the wound bed from accumulation of exudates and reduce the frequency of replacement. Moreover, the good biocompatibility of HA-g-Pu polymers were confirmed by skin irritation, cytotoxicity, cell proliferation and hemolysis test. Compared with the natural healing, the HA-g-Pu films promoted the wound healing. HA of HA-g-Pu polymers played an important role in the wound healing response. Furthermore, the HA-g-Pu polymers appeared a certain coagulation function and obtained a relative rapid hemostasis ability which might be attribute to heal wound.