Time-Programmed Delivery of Sorafenib and Anti-CD47 Antibody via a Double-Layer-Gel Matrix for Postsurgical Treatment of Breast Cancer

The highly immunosuppressive microenvironment after surgery has a crucial impact on the recurrence and metastasis in breast cancer patients.Programmable delivery of immunotherapy-involving combinations through a single drug delivery system is highly promising,yet greatly challenging,to reverse postoperative immunosuppression.Here,an injectable hierarchical gel matrix,composed of dual lipid gel(DLG)layers with different soybean phosphatidylcholine/glycerol dioleate mass ratios,was developed to achieve the time-programmed sequential delivery of combined cancer immunotherapy.The outer layer of the DLG matrix was thermally responsive and loaded with sorafenib-adsorbed graphene oxide(GO)nanoparticles.GO under manually controlled near-infrared irradiation generated mild heat and provoked the release of sorafenib first to reeducate tumor-associated macrophages(TAMs)and promote an immunogenic tumor microenvironment.The inner layer,loaded with anti-CD47 antibody(aCD47),could maintain the gel state for a much longer time,enabling the sustained release of aCD47 afterward to block the CD47-signal regulatory proteinα(SIRPα)pathway for a long-term antitumor effect.In vivo studies on 4T1 tumor-bearing mouse model demonstrated that the DLG-based strategy efficiently prevented tumor recurrence and metastasis by locally reversing the immunosuppression and synergistically blocking the CD47-dependent immune escape,thereby boosting the systemic immune responses.

Nanomedicine potentiates mild photothermal therapy for tumor ablation

The booming photothermal therapy(PTT)has achieved great progress in non-invasive oncotherapy,and paves a novel way for clinical oncotherapy.Of note,mild temperature PTT(mPTT)of 42–45°C could avoid treatment bottleneck of the traditional PTT,including nonspecific injury to normal tissues,vasculature and host antitumor immunity.However,cancer cells can resist mPTT via heat shock response and autophagy,thus leading to insufficient mPTT monotherapy to ablate tumor.To overcome the deficient antitumor efficacy caused by thermo-resistance of cancer cells and mono mPTT,synergistic therapies towards cancer cells have been conducted with mPTT.This review summarizes the recent advances in nanomedicine-potentiated mPTT for cancer treatment,including strategies for enhanced single-mode mPTT and mPTT plus synergistic therapies.Moreover,challenges and prospects for clinical translation of nanomedicine-potentiated mPTT are discussed.

Natural polysaccharide-based smart CXCR4-targeted nano-system for magnified liver fibrosis therapy

Activated hepatic stellate cells(aHSCs),the main source of extracellular matrix deposition,are key targets in liver fibrosis.However,no effective drug specific to aHSCs has been clinically applied due to poor drug delivery efficiency.Herein,we designed a CXC chemokine receptor 4(CXCR4)-targeted reactive oxygen species(ROS)-responsive platform AMD-Dex-ROS-responsive-sorafenib(ARS)based on natural polysaccharide and thioctic acid frame,which can deliver anti-fibrosis drug represented by sorafenib specifically to aHSCs on account of CXCR4 over-expression on aHSCs,and smartly disassemble via ROS-responsive thioketal rupture relying on high intracellular ROS in HSCs,realized on-demand drug release and effective liver fibrosis reversion.Notably,in this platform,the CXCR4 antagonist AMD3100 not only enhanced aHSCs targeting efficiency of sorafenib but also effectively magnified the aHSCs elimination of sorafenib by blocking stroma cell derived factor-1(SDF-1)/CXCR4-induced aHSCs protection,resulting in synergistic anti-fibrosis effect.The platform provided a new approach for drug delivery system design and liver fibrosis treatment.

Leveraging nano-engineered mesenchymal stem cells for intramedullary spinal cord tumor treatment

Intramedullary spinal cord tumor(IMSCT)is comparatively rare malignant tumor in the central nervous system and is very difficult accessible by conventional chemotherapy regimen.Currently,there are very limited researches for IMSCT treatment using nanomedicine.To fill this gap,we originally reported a targeted strategy by leveraging nano-engineered mesenchymal stem cells(MSCs)for synergistic antiIMSCT treatment.In this study,two mode drugs paclitaxel(PTX)and metformin(MET)were co-loaded in maleimide-modified poly(lactic-co-glycolicacid)(PLGA-MAL)nanoparticles,which were further conjugated onto MSCs surface via the thioether bond formed between PLGA-MAL and MSCs without affecting the migration ability of MSCs.Owing to the excellent tumor tropism and penetrability of MSCs and good biodegradability of PLGA,the designed drug delivery platform could accurately target IMSCT sites to exert long-term synergistic antitumor efficacy,exhibiting promising research value for alternative IMSCT management beyond surgery.

Reversing the PAI-1-induced fibrotic immune exclusion of solid tumor by multivalent CXCR4 antagonistic nano-permeator

Fibrosis is one of the key factors that lead to the immune exclusion of solid tumors.Although degradation of fiber is a promising strategy,its application was still bottlenecked by the side effects of causing metastasis,resulting in the failure of immunotherapy.Here,we developed an antimetastatic polymer(HPA)for the delivery of chemo-drug and antifibrotic siPAI-1 to form the nano-permeator.Nano-permeator shrank after protonation and deeply penetrated into the tumor core to down-regulate the expression of PAI-1 for antifibrosis,and further promoted the sustained infiltration and activation of T cells for killing tumor cells.Moreover,metastasis after fiber elimination was prevented by multivalent CXCR4 antagonistic HPA to reduce the attraction of CXCL12 secreted by distant organs.The administration of stroma-alleviated immunotherapy increased the infiltration of CD8+T cells to 52.5%in tumor tissues,inhibiting nearly 90%metastasis by HPA in distant organs.The nano-permeator reveals the mechanism and correlation between antifibrosis and antimetastasis and was believed to be the optimizing immunotherapy for solid fibrotic tumors.