sAPPα Peptide Promotes Damaged Microglia to Clear Alzheimer's Amyloid-ß via Restoring Mitochondrial Function.

Alzheimer's disease (AD) is an age-related neurodegenerative disease with amyloid-ß (Aß) deposition as the main pathological feature. It's an important challenge to find new ways to clear Aß from the brain. The soluble amyloid precursor protein α (sAPPα) is a neuroprotective protein and can attenuate neuronal damage, including toxic Aß. However, the regulatory role of sAPPα in non-neuronal cells, such as microglia, is less reported and controversial. Here, we showed that sAPPα promoted the phagocytosis and degradation of Aß in both normal and damaged microglia. Moreover, the function of damaged microglia was improved by the sAPPα through normalizing mitochondrial function. Furthermore, the results of molecular docking simulation showed that sAPPα had a good affinity with Aß. We preliminarily reveal that sAPPα is similar to antibodies and can participate in the regulation of microglia phagocytosis and degradation of Aß after binding to Aß. sAPPα is expected to be a mild and safe peptide drug or drug carrier for AD.

Research progress in leveraging biomaterials for enhancing NK cell immunotherapy. / 生物材料增效NKç»†èƒžå ç–«ç–—æ³•ç ”ç©¶è¿›å±•.

NK cell immunotherapy is a promising antitumor therapeutic modality after the development of T cell immunotherapy. Structural modification of NK cells with biomaterials may provide a precise, efficient, and low-cost strategy to enhance NK cell immunotherapy. The biomaterial modification of NK cells can be divided into two strategies: surface engineering with biomaterials and intracellular modification. The surface engineering strategies include hydrophobic interaction of lipids, receptor-ligand interaction between membrane proteins, covalent binding to amino acid residues, click reaction and electrostatic interaction. The intracellular modification strategies are based on manipulation by nanotechnology using membranous materials from various sources of NK cells (such as exosome, vesicle and cytomembranes). Finally, the biomaterials-based strategies regulate the recruitment, recognition and cytotoxicity of NK cells in the solid tumor site in situ to boost the activity of NK cells in the tumor. This article reviews the recent research progress in enhancing NK cell therapy based on biomaterial modification, to provide a reference for further researches on engineering NK cell therapy with biomaterials.

Using bio-orthogonally catalyzed lethality strategy to generate mitochondria-targeting anti-tumor metallodrugs in vitro and in vivo.

Synthetic lethality was proposed nearly a century ago by geneticists and recently applied to develop precision anti-cancer therapies. To exploit the synthetic lethality concept in the design of chemical anti-cancer agents, we developed a bio-orthogonally catalyzed lethality (BCL) strategy to generate targeting anti-tumor metallodrugs both in vitro and in vivo. Metallodrug Ru-rhein was generated from two non-toxic species Ru-N3 and rhein-alkyne via exclusive endogenous copper-catalyzed azide alkyne cycloaddition (CuAAC) reaction without the need of an external copper catalyst. The non-toxic species Ru-arene complex Ru-N3 and rhein-alkyne were designed to perform this strategy, and the mitochondrial targeting product Ru-rhein was generated in high yield (>83%) and showed high anti-tumor efficacy in vitro. This BCL strategy achieved a remarkable tumor suppression effect on the tumor-bearing mice models. It is interesting that the combination of metal-arene complexes with rhein via CuAAC reaction could transform two non-toxic species into a targeting anti-cancer metallodrug both in vitro and in vivo, while the product Ru-rhein was non-toxic towards normal cells. This is the first example that exclusive endogenous copper was used to generate metal-based anti-cancer drugs for cancer treatment. The anti-cancer mechanism of Ru-rhein was studied and autophagy was induced by increased reactive oxygen species and mitochondrial damage. The generality of this BCL strategy was also studied and it could be extended to other metal complexes such as Os-arene and Ir-arene complexes. Compared with the traditional methods for cancer treatment, this work presented a new approach to generating targeting metallodrugs in vivo via the BCL strategy from non-toxic species in metal-based chemotherapy.

Fluorine assembly nanocluster breaks the shackles of immunosuppression to turn the cold tumor hot.

Clinical investigations have shown that a nonimmunogenic "cold" tumor is usually accompanied by few immunopositive cells and more immunosuppressive cells in the tumor microenvironment (TME), which is still the bottleneck of immune activation. Here, a fluorine assembly nanocluster was explored to break the shackles of immunosuppression, reawaken the immune system, and turn the cold tumor "hot." Once under laser irradiation, FS@PMPt produces sufficient reactive oxygen species (ROS) to fracture the ROS-sensitive linker, thus releasing the cisplatin conjugated PMPt to penetrate into the tumors and kill the regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Meanwhile, ROS will induce potent immunogenic cell death (ICD) and further promote the accumulation of dendritic cells (DCs) and T cells, therefore not only increasing the infiltration of immunopositive cells from the outside but also reducing the immunosuppressive cells from the inside to break through the bottleneck of immune activation. The FS@PMPt nanocluster regulates the immune process in TME from negative to positive, from shallow to deep, to turn the cold tumor into a hot tumor and provoke a robust antitumor immune response.

GSH depletion liposome adjuvant for augmenting the photothermal immunotherapy of breast cancer.

The high redox level of tumor microenvironment inhibits the oxidation treatment and the immune response. Here, we innovatively develop maleimide liposome (ML) adjuvants to promote immunogenic cell death (ICD) induction and dendritic cells (DCs) maturation by glutathione (GSH) depletion for augmenting the photothermal immunotherapy of breast cancer. The ML effectively depletes the intracellular GSH and up-regulates reactive oxygen species (ROS) in both tumor cells and DCs. In tumor cells, the ROS boosted the ABTS·+ production to activate photothermal-induced ICD. In DCs, it relieved the immunosuppression, promoting DC maturation (57%) and antigen presenting. As a result of the ML assistant, the therapeutic systems improved the infiltration of CD8+ T cells to 53% in tumor tissues, eliciting strong abscopal effect and antimetastasis effect. The MLs were believed to be a superior candidate of adjuvants for enhancing immune response and cancer therapeutic efficacy.

"Star" miR-34a and CXCR4 antagonist based nanoplex for binary cooperative migration treatment against metastatic breast cancer.

Invasion and metastasis of tumor cells is one of the major obstacles in cancer therapy. The process of tumor metastasis and diffusion is coordinated by multiple pathways associated with chemokine signals and migration microenvironment. In our previous work, chemokine CXC receptor 4 (CXCR4) antagonists showed significant anti-metastatic effects by blocking the CXCR4/stromal cell-derived factor-1(SDF-1) axis in pancreatic cancer and breast cancer. Here, we proposed to achieve migration chain-treatment for metastatic tumors by introducing a cell adhesion molecules CD44 inhibitor (Star miR-34a) to deprive of cell migration capability on the basis of CXCR4 antagonism (cyclam monomer, CM). Dextrin modified 1.8 k PEI with CM-end was prepared to deliver therapeutic miR-34a (named DPC/miR-34a) for efficient anti-metastasis by downregulating adhesion protein CD44 and targeting the CXCR4/SDF-1 axis. Additionally, reduced expression of the anti-apoptotic protein Bcl2 caused by miR-34a could enhance the anti-tumor efficacy of DPC/miR-34a nanoplex administration. Compared with inhibition of the CXCR4/SDF-1 axis or CD44 expression, the multidimensional therapy (DPC/miR-34a) exhibited considerable suppression of cancer cell invasion as assessed by an in vitro cell invasion assay and in vivo anti-metastasis model. Moreover, DPC/miR-34a demonstrated a superior antitumor and anti-metastatic efficacy both in lung metastatic model and orthotopic MDA-MB-231 tumor models, thus providing an efficient approach for combating metastatic tumors.

Dual-Mode Avocado-like All-Iron Nanoplatform for Enhanced T1/T2 MRI-Guided Cancer Theranostic Therapy.

Development of T1/T2 dual-mode MRI contrast agents that can also treat cancer is an attractive prospect for personalized precision medicine. Unfortunately, conventional contrast agents can suffer from toxicity and lack any ability to treat cancer. An all-iron T1/T2 MR imaging agent with photothermal and drug delivery capability would overcome these issues. Here, an avocado-like Fe3+/Fe2O3 composed T1-T2 dual-mode contrast agent based on Fe-TA coordination network (CNMN) is developed. This material possesses suitable longitudinal and transverse relaxation coefficients. Moreover, the strong heat generation property of Fe-TA endows CNMN with the capability to act as a potent photothermal agent. Furthermore, CNMN can also act as an effective delivery platform for the chemotherapeutic drug doxorubicin (DOX) to achieve high effective chemo-photothermal combination therapy. The work demonstrates reliable T1-T2 MRI-guided chemo-photothermal therapy for safe and effective clinical application.

Targeting pulmonary tumor microenvironment with CXCR4-inhibiting nanocomplex to enhance anti-PD-L1 immunotherapy.

Anti-programmed cell death 1 ligand 1 (PD-L1) therapy is extraordinarily effective in select patients with cancer. However, insufficient lymphocytic infiltration, weak T cell-induced inflammation, and immunosuppressive cell accumulation in the tumor microenvironment (TME) may greatly diminish the efficacy. Here, we report development of the FX@HP nanocomplex composed of fluorinated polymerized CXCR4 antagonism (FX) and paclitaxel-loaded human serum albumin (HP) for pulmonary delivery of anti-PD-L1 small interfering RNA (siPD-L1) to treat orthotopic lung tumors. FX@HP induced T cell infiltration, increased expression of calreticulin on tumor cells, and reduced the myeloid-derived suppressor cells/regulatory T cells in the TME, thereby acting synergistically with siPD-L1 for effective immunotherapy. Our work suggests that the CXCR4-inhibiting nanocomplex decreases tumor fibrosis, facilitates T cell infiltration and relieves immunosuppression to modulate the immune process to improve the objective response rate of anti-PD-L1 immunotherapy.

ATP-Charged Nanoclusters Enable Intracellular Protein Delivery and Activity Modulation for Cancer Theranostics.

Protein drugs own a large share in the market and hold great prospects for the treatment of many diseases. However, the available protein drugs are limited to the extracellular target, owing to the inefficient transduction and activity modulation of proteins targeting intracellular environment. In this study, we constructed ATP-charged platforms to overcome the above-mentioned barriers for cancer theranostics. The phenylboronic acid-modified polycations (PCD) were synthesized to assemble with enzymes and shield its activity in the blood circulation. When the PCD nanoclusters reached tumor site, they effectively transported the enzymes into the cells, followed by recovering its catalytic activity after being charged with ATP. Importantly, the cascaded enzyme systems (GOx&HRPA) selectively induced starvation therapy as well as photoacoustic imaging of tumor. Our results revealed that the intelligent nanoclusters were broadly applicable for protein transduction and enzyme activity modulation, which could accelerate the clinical translation of protein drugs toward intracellular target.

Tissue-Specific Regulation of Reactive Oxygen Species by an ATP-Responsive Nanoregulator Enhances Anticancer Efficacy and Reduces Anthracycline-Induced Cardiotoxicity.

Chemotherapy plays an important role in cancer treatment, yet its clinical application is inhibited by side effects. Chemotherapeutic agents accumulate at nonspecific sites and induce oxidative stress damage in noncancer tissues. A selective approach would be ideal, which would not only enhance anticancer efficacy in the tumor sites but also reduce chemotherapy-induced adverse effects on normal tissues. Therefore, we reported an adenosine-5'-triphosphate (ATP)-responsive oxidative stress nanoregulator (DePQu-DOX) to achieve the tissue-specific therapy. The DePQu-DOX NPs coloading doxorubicin (DOX) and quercetin (Qu) enhanced oxidative stress in murine breast cancer cells and scavenged DOX-induced oxygen free radicals in normal cardiac myocytes and podocytes. The released Qu could accelerate free radical scavenging more efficiently in oxygen-rich myocardium than in hypoxic tumors. Additionally, the ATP-specific responsiveness of nanocarriers enable cargos to selectively accumulate at tumor sites and decline the accumulation amount at normal tissues, resulting in lower system toxicity and improved anticancer effects. In vitro and in vivo experiments showed that this oxidative stress nanoregulator could efficiently protect normal tissues and significantly inhibit tumor growth. This study suggests that nanomedicine-mediated oxidative stress regulation could provide selective tumor therapeutics and reduce anthracycline-induced system toxicity.

A pH-sensitive coordination polymer network-based nanoplatform for magnetic resonance imaging-guided cancer chemo-photothermal synergistic therapy.

Developing various kinds of nanoplatforms with integrated diagnostic and therapeutic functions would be significant for imaging-guided precision treatment of cancer. However, it is still a challenge to organically integrate therapeutic and imaging components into a single nano-system rather than simply mixing. Herein, an iron-gallic acid network-based nanoparticle (Fe-GA@PEG-PLGA) was designed for magnetic resonance imaging (MRI)-guided chemo-photothermal synergistic therapy of tumors. The tumor spatial location and size information can be accurately achieved due to T1 MRI based on Fe3+ coordination with GA in Fe-GA network. Furthermore, the nanoparticle exhibited extraordinary photostability and photothermal therapy capacity exceeded 42 °C within 100 s under 808 nm laser irradiation. Meanwhile, the Fe-GA polymeric network can be disassembled in tumor acidic environment and the released drug GA can induce apoptosis. This study demonstrated that the Fe-GA network-based nanoparticle is a promising diagnostic and therapeutic agent for theranostic application and further clinic translation.

H2O2-activated oxidative stress amplifier capable of GSH scavenging for enhancing tumor photodynamic therapy.

Photodynamic therapy (PDT) is a clinically approved cancer treatment approach that relies on the generation of excess reactive oxygen species (ROS) to eradicate tumor cells by inducing oxidative stress. Unfortunately, if the tumor's endogenous glutathione (GSH) is overexpressed, it will eliminate the ROS and restrict the therapeutic efficacy of PDT. Herein, we report a H2O2-activated oxidative stress amplifier (OSA) for enhancing the ROS generation for PDT via GSH scavenging. Cinnamaldehyde (Cin) and chlorin e6 (Ce6) were applied as the GSH scavenger and photosensitizer, respectively, which were assembled with the ROS-responsive amphipathic polymer (DPL) to form DPL@CC micelles as the OSA. In the circulation of blood, the OSA can effectively protect the Cin from albumin binding to retain its GSH depletion ability. Once the OSA reached the tumor site, the high level of H2O2 triggered the degradation of DPL and led to the release of Cin and Ce6. Subsequently, the released Cin reacted with the intracellular GSH by Michael Addition and downregulated the GSH level to about 18.9%, versus untreated cells, to weaken the anti-oxidation ability of tumor cells. Thus, it provided a suitable environment for PDT to obtain an amplifying effect on oxidative stress and superior anti-cancer efficacy of 94% growth inhibition. The preparation of the H2O2-activated oxidative stress amplifier is a convincing strategy for promoting intracellular ROS generation and enhancing the tumor PDT efficacy, which could also augment the clinical application of PDT.

Charge-switchable polymeric complex for glucose-responsive insulin delivery in mice and pigs.

Glucose-responsive insulin delivery systems with robust responsiveness that has been validated in animal models, especially in large animal models, remain elusive. Here, we exploit a new strategy to form a micro-sized complex between a charge-switchable polymer with a glucose-sensing moiety and insulin driven by electrostatic interaction. Both high insulin loading efficiency (95%) and loading capacity (49%) can be achieved. In the presence of a hyperglycemic state, the glucose-responsive phenylboronic acid (PBA) binds glucose instantly and converts the charge of the polymeric moiety from positive to negative, thereby enabling the release of insulin from the complex. Adjusting the ratio of the positively charged group to PBA achieves inhibited insulin release from the complex under normoglycemic conditions and promoted release under hyperglycemic conditions. Through chemically induced type 1 diabetic mouse and swine models, in vivo hyperglycemia-triggered insulin release with fast response is demonstrated after the complex is administrated by either subcutaneous injection or transdermal microneedle array patch.

A nanoscale photothermal agent based on a metal-organic coordination polymer as a drug-loading framework for effective combination therapy.

Metallic materials are widely emerging as photothermal agents owing to their superior photothermal transduction efficiency and satisfactory photostability. In this study, an iron-based coordination polymer (Fe-CNP) loaded with doxorubicin (DOX) was assessed as a dual-function agent for photothermal therapy (PTT) and tumor-targeted chemotherapy. Fe-CNPs were synthesized by a one-step coordination reaction between Fe3+, hydrocaffeic acid, and dopamine-modified hyaluronic acid. A drug-loading method was developed to entrap DOX within Fe-CNPs through the formation of coordination bonds by Fe3+ and DOX (Scheme 1). DOX release was rapidly triggered in the cellular acidic environment and further enhanced by hyperpyrexia in the part of tumor, which will kill the remaining tumor cells after PTT. Animal experiments demonstrated complete inhibition of tumor growth without recurrence in 21 days after injection of DOX@Fe-CNPs with NIR laser irradiation. These results confirmed the enhanced anti-tumor efficiency of the chemo-photothermal nanosystem. Our work may reveal a photothermal coordination polymer as a drug-loading framework and highlight the development of metal-organic materials in combined chemo-photothermal therapy. STATEMENT OF SIGNIFICANCE: Photothermal therapy (PTT), which could directly act on tumors, has been considered as a promising treatment method for cancer. The combination of PTT with chemotherapy is attracting tremendous attention because such advanced application can achieve personalized precise medicine. Unfortunately, most PTT materials have photobleaching property, which results in reduced photothermal efficiency. Furthermore, their clinical applications also suffer from low loading capacity of chemotherapeutic drugs or nonbiodegradability in the biological system. In this study, we hypothesized that iron-based coordination polymers (Fe-CNPs) could function dually as agents to deliver both PTT and tumor-targeted chemotherapy by coordination loading of the chemotherapeutic drug doxorubicin (DOX). Our work may open up new avenues to rationally design versatile platforms for photothermal-chemotherapy to obtain synergistically enhanced therapeutic efficacy.

Biomimetic Hybrid Nanozymes with Self-Supplied H+ and Accelerated O2 Generation for Enhanced Starvation and Photodynamic Therapy against Hypoxic Tumors.

Nanozymes as artificial enzymes that mimicked natural enzyme-like activities have received great attention in cancer diagnosis and therapy. Biomimetic nanozymes require more consideration regarding complicated tumor microenvironments to mimic biological enzymes, thus achieving superior nanozyme activity in vivo. Here we report a biomimetic hybrid nanozyme (named rMGB) which integrates natural enzyme glucose oxidase (GOx) with nanozyme manganese dioxide (MnO2) by mutual promotion for maximizing the enzymatic activity of MnO2 and GOx. Under hypoxia environment, we observed that MnO2 could react with endogenous H2O2 to produce O2 for enhancing the catalytic efficiency of GOx for starvation therapy. Meanwhile, we confirmed that glucose oxidation generated gluconic acid and further improved the catalytic efficiency of MnO2 subsequently. The biochemical reaction cycle, consisting of MnO2, O2, GOx, and H+, was triggered by the tumor microenvironment and accelerated each other so as to achieve self-supplied H+ and accelerate O2 generation, enhancing the starvation therapy, alleviating tumor hypoxia and accelerating the reactive oxygen species generation in photodynamic therapy. This biomimetic hybrid nanozyme would further facilitate the development of biological nanozymes for cancer treatment.

Photoactivated Lysosomal Escape of a Monofunctional PtII Complex Pt-BDPA for Nucleus Access.

A photosensitizing monofunctional Pt complex, Pt-BDPA, was prepared with a BODIPY chromophore. Apart from its DNA binding ability, this complex displays emission at ca. 578 nm and a singlet oxygen quantum yield of 0.133. Confocal imaging revealed that this complex was sequestered in lysosomes via endocytosis in the dark, preventing its access to the nucleus. Profiting from its photoinduced ROS generation ability, this complex undergoes lysosomal escape to access the nucleus upon photoirradiation. The photoinduced ROS still cause a drop in intracellular GSH, favoring the stability of Pt-BDPA and contributing to its nuclear DNA accessibility. This complex displayed distinct cytotoxicity to all tested tumor cell lines upon photoirradiation, and the IC50 values were ca. 3-6 µm, which are distinctly lower than those found with only dark incubation (IC50 >50 µm). These results are consistent with photoactivated lysosomal escape of this photosensitizing Pt complex to access the nucleus.

Light-Induced ROS Generation and 2-DG-Activated Endoplasmic Reticulum Stress by Antitumor Nanosystems: An Effective Combination Therapy by Regulating the Tumor Microenvironment.

A multimodal cancer therapeutic nanoplatform is reported. It demonstrates a promising approach to synergistically regulating the tumor microenvironment. The combination of intracellular reactive oxygen species (ROS) generated by irradiation of photosensitizer and endoplasmic reticulum (ER) stress induced by 2-deoxy-glucose (2-DG) has a profound effect on necrotic or apoptotic cell death. Especially, targeting metabolic pathway by 2-DG is a promising strategy to promote the effect of photodynamic therapy and chemotherapy. The nanoplatform can readily release its cargoes inside cancer cells and combines the advantages of ROS-sensitive releasing chemotherapeutic drugs, upregulating apoptosis pathways under ER stress, light-induced generation of cytotoxic ROS, achieving tumor accumulation, and in vivo fluorescence imaging capability. This work highlights the importance of considering multiple intracellular stresses as design parameters for nanoscale functional materials in cell biology, immune response, as well as medical treatments of cancer, Alzheimer's disease, etc.

ATP-activated decrosslinking and charge-reversal vectors for siRNA delivery and cancer therapy.

Stimuli-responsive polycations have been developed for improved nucleic acid transfection and enhanced therapeutic efficacy. The most reported mechanisms for controlled release of siRNA are based on polyelectrolyte exchange reactions in the cytoplasm and the degradation of polycations initiated by specific triggers. However, the degradation strategy has not always been sufficient due to unsatisfactory kinetics and binding of cationic fragments to siRNA, which limits the gene silencing effect. In this study, a new strategy that combines degradation and charge reversal is proposed. Methods: We prepared a polycation (CrossPPA) by crosslinking of phenylboronic acid (PBA)-grafted 1.8k PEI with alginate. It was compared with 25k PEI, 1.8k PEI and 1.8k PEI-PBA on siRNA encapsulation, ATP-responsive behavior and mechanism, cytotoxicity, cell uptake, siRNA transfection, in vivo biodistribution and in vivo anti-tumor efficacy. The in vitro and in vivo experiments were performed on 4T1 murine breast cancer cells and 4T1 tumor model separately. Results: The crosslinking strategy obviously improve the siRNA loading ability of 1.8k PEI. We validated that intracellular levels of ATP could trigger CrossPPA disassembly and charge reversal, which resulted in efficient and rapid siRNA release due to electrostatic repulsion. Besides, CrossPPA/siRNA showed strong cell uptake in 4T1 cells compared with 1.8k PEI/siRNA. Notably, the cytotoxicity of CrossPPA was pretty low, which was owing to its biodegradability. Furthermore, the crosslinked polyplexes significantly enhanced siRNA transfection and improved tumor accumulation. The high gene silencing ability of CrossPPA polyplex led to strong anti-tumor efficacy when using Bcl2-targeted siRNA. Conclusion: These results indicated that the ATP-triggered disassembly and charge reversal strategy provided a new way for developing stimuli-responsive siRNA carriers and showed potential for nucleic acid delivery in the treatment of cancer.

Charge and Assembly Reversible Micelles Fueled by Intracellular ATP for Improved siRNA Transfection.

Hydrophobic modification on polycations were commonly used to improve the stability and transfection efficiency of polyplexes. However, the improved stability often means undesired release of the encapsulated siRNA, limiting the application of cationic micelles for siRNA delivery. The current strategy of preparing bioresponsive micelles based on the cleavage of sensitive linkages between polycation and hydrophobic part was far from sufficient, owing to the siRNA binding of the separated polycations from micelles leading to the incomplete release of siRNA. In this study, we propose a new strategy by the combination of micelles disassembly and separated polycations charge reversal. FPBA (3-fluoro-4-carboxyphenylboronic acid) grafted PEI 1.8 k (polyethylenimine) as the polycations of PEI-FPBA and dopamine (with diol-containing moiety) conjugated with cholesterol as the hydrophobic part (Chol-Dopa). The PFCDM micelles was assembled by PEI-FPBA and Chol-Dopa, based on the FPBA-Dopa conjugation. The prepared PFCDM showed strong siRNA loading ability and superior stability in the presence of PBS or serum. Besides, the PFCDM exhibited excellent ATP sensibility. The intracellular ATP could effectively trigger the disassembly of micelles and charge reversal of PEI-FPBA, resulting in the burst release of siRNA in the cytosol. With the property of extracellular stability and intracellular instability, PFCDM displayed good performance on in vitro and in vivo luciferase silencing on 4T1 cells. It should also be noted that the assembly of low molecular weight PEI was relatively safe to cells compared with 25 k PEI. To sum up, the ATP-fueled assembly and charge reversible micelles gave examples for polyplexes to achieve better stability and on demand cargo release at the same time and shows potential to be used for in vitro and in vivo siRNA transfection.

A multifunctional ternary Cu(II)-carboxylate coordination polymeric nanocomplex for cancer thermochemotherapy.

Metal-based photothermal therapy has been widely used in the biomedicine field and includes gold nanoparticles, silver nanoparticles and copper sulfide nanoparticles. Furthermore, the coordination bonding-based metal nanocomplex is a new generation of photothermal agents for cancer therapy due to its high photothermal transduction efficiency, good biocompatibility, biodegradation and bioactivity. In this study, we designed a coordination bonding-based copper (Cu(II))-carboxylate ternary architecture, which consists of a conjugate dopamine-modified nontoxic hyaluronic acid, copper ions and citric acid. When the Cu(II) coordinated with the carboxyl groups, the splitting d orbitals energy gap of Cu(II) and the capability of electron transition were enhanced, which can increase the extinction ability in the near-infrared region for enhancing photothermal therapy. Moreover, the degradation of hyaluronic acid by hyaluronidase highly expressed in the tumor microenvironment led to the release of Cu-citric acid complexes, thus exhibiting an additional chemotherapeutic effect. The nanocomplexes possessed high-performance photothermal conversion, determined to be 21.3%. The solution could be easily heated to above 42 °C, which was sufficient to ablate the cancer cells. An obvious decrease in cell viability was observed in B16F10 cells incubated with the nanocomplexes under laser at the lower concentration of 20 µg/mL Cu(II). Upon near-infrared laser irradiation, the nanocomplexes showed high photothermal therapy and chemotherapeutic efficacy for breast cancer in vivo. This study demonstrated that the Cu(II)-carboxylate coordination nanocomplex is a promising new effective and facilely prepared thermochemotherapy agent for combination therapy against cancer.