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Checkpoint blockade immunotherapy has shown great potential in clinical cancer therapy, but the body's systemic immune must be fully activated and generates a positive tumor-specific immune cell response. In this work, we demonstrate the design of the immune-adjuvant nanodrug carriers on the basis of poly(ethylene glycol)- block-poly(lactic- co-glycolic acid) copolymer-encapsulated FeO superparticles (SPs), in which imiquimod (R837), a kind of Toll-like receptor 7 agonist, is loaded. The nanodrug carriers are defined as FeO-R837 SPs. The multitasking FeO-R837 SPs can destroy the 4T1 breast tumor by photothermal therapy (PTT) under near-infrared laser irradiation to generate the tumor-associated antigens because of the high efficiency of tumor magnetic attraction ability and photothermal effect. The PTT also triggers the release of R837 as the adjuvant to trigger a strong antitumor immune response. By further combining with the checkpoint blockade adjusted by programmed death ligand 1 (PD-L1) antibody, the FeO-R837 SP-involved PTT cannot only eliminate the primary tumors but also prevent tumor metastasis to lungs/liver. Meanwhile, this synergistic therapy also shows abscopal effects by completely inhibiting the growth of untreated distant tumors through effectively triggering the tumors infiltrated by CD45 leukocytes. Such findings suggest that FeO-R837 SP-involved PTT can significantly potentiate the systemic therapeutic efficiency of PD-L1 checkpoint blockade therapy by activating both innate and adaptive immune systems in the body.

BackgroundRepair of nonunion critical-sized bone defects is a significant clinical challenge all over the world. Construction of osteogenic microenvironment that provides osteoconductive and osteoinductive signals is a leading strategy.Materials and methodsIn the present study, ascorbic acid (AA) and β-glycerophosphate disodium salt hydrate (β-GP) modified biomimetic gelatin/hydroxyapatite (GH) nanofibrous scaffolds were developed by electrospinning. Then the scaffolds were crosslinked by N-hydroxysulfo-succinimide sodium salt (NHS) and 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC). The morphology of the non-crosslinked and crosslinked scaffolds was evaluated by scanning electron microscope (SEM). Fourier transform infrared spectroscopy (FT-IR) was used to assess the interacting model between the small molecules and GH scaffold. Then MTT, Alamar Blue, and CCK8 assays were used to investigate the biocompatibility of the various crosslinked scaffolds. Subsequently, the osteogenic genes expression of bone marrow stromal cells (BMSCs) cultured on the scaffolds were detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Finally, the crosslinked scaffolds were implanted in a rat calvarial defect model to assess the osteogenic effects in vivo.ResultsSEM results showed that the various scaffolds presented extracellular matrix (ECM)-like fibrous porous structure. (FT-IR) spectrum indicated that AA and β-GP were covalently bonded with GH scaffolds. The MTT, Alamar Blue, and CCK8 assays demonstrated that all the scaffolds can support BMSCs’ growth well. The qRT-PCR results showed that the expression level of Alp and Runx2 in BMSCs on GH/A/B scaffold was about 3.5- and 1.5-fold, respectively, compared with that of GH group on day 7. The results also showed that AA- and β-GP-modified GH scaffolds can significantly induce the higher levels of osteogenic gene expression in a temporal specific manner. Importantly, AA and β-GP synergistically promoted osteoblast differentiation in vitro and dramatically induced bone regeneration in vivo. Impressively, AA and β-GP dual modified GH nanofibrous scaffold could serve as a template for guiding bone regeneration and the bone defects were almost repaired completely (94.28%±5.00%) at 6 weeks. Besides, single AA or β-GP-modified GH nanofibrous scaffolds could repair 62.95%±9.39% and 66.56%±18.45% bone defects, respectively, at 12 weeks in vivo. In addition, AA and β-GP exhibit an anti-inflammatory effect in vivo.ConclusionOur data highlighted that, AA, β-GP, and GH nanofibers created a fine osteoconductive and osteoinductive microenvironments for bone regeneration. We demonstrated that AA and β-GP dual modified GH nanofiber is a versatile bone tissue engineering scaffold.

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