A red blood cell-derived bionic microrobot capable of hierarchically adapting to five critical stages in systemic drug delivery.

The tumour-targeting efficiency of systemically delivered chemodrugs largely dictates the therapeutic outcome of anticancer treatment. Major challenges lie in the complexity of diverse biological barriers that drug delivery systems must hierarchically overcome to reach their cellular/subcellular targets. Herein, an "all-in-one" red blood cell (RBC)-derived microrobot that can hierarchically adapt to five critical stages during systemic drug delivery, that is, circulation, accumulation, release, extravasation, and penetration, is developed. The microrobots behave like natural RBCs in blood circulation, due to their almost identical surface properties, but can be magnetically manipulated to accumulate at regions of interest such as tumours. Next, the microrobots are "immolated" under laser irradiation to release their therapeutic cargoes and, by generating heat, to enhance drug extravasation through vascular barriers. As a coloaded agent, pirfenidone (PFD) can inhibit the formation of extracellular matrix and increase the penetration depth of chemodrugs in the solid tumour. It is demonstrated that this system effectively suppresses both primary and metastatic tumours in mouse models without evident side effects, and may represent a new class of intelligent biomimicking robots for biomedical applications.

Self-Regenerating Photothermal Agents for Tandem Photothermal and Thermodynamic Tumor Therapy.

Small molecule-based photothermal agents (PTAs) hold promising future for photothermal therapy; however, unexpected inactivation exerts negative impacts on their application clinically. Herein, a self-regenerating PTA strategy is proposed by integrating 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical cation (ABTS•+) with a thermodynamic agent (TDA) 2,2'-azobis[2-(2-imidazolin-2-yl) propane] dihydrochloride (AIPH). Under NIR laser, the photothermal effect of ABTS•+ accelerates the production of alkyl radicals by AIPH, which activates the regeneration of ABTS•+, thus creating a continuous positive feedback loop between photothermal and thermodynamic effects. The combination of ABTS•+ regeneration and alkyl radical production leads to the tandem photothermal and thermodynamic tumor therapy. In vitro and in vivo experiments confirm that the synergistic action of thermal ablation, radical damage, and oxidative stress effectively realizes tumor suppression. This work offers a promising approach to address the unwanted inactivation of PTAs and provides valuable insights for optimizing combination therapy.

Three-in-One Peptide Prodrug with Targeting, Assembly and Release Properties for Overcoming Bacterium-Induced Drug Resistance and Potentiating Anti-Cancer Immune Response.

The presence of bacteria in tumor results in chemotherapeutic drug resistance and weakens the immune response in colorectal cancer. To overcome bacterium-induced chemotherapeutic drug resistance and potentiate antitumor immunity, herein a novel molecule Biotin-Lys(SA-Cip-OH)-Lys(SA-CPT)-Phe-Phe-Nap (Biotin-Cip-CPT-Nap) is rationally designed containing four functional motifs (i.e., a biotin motif for targeting, Phe-Phe(-Nap) motif for self-assembly, ciprofloxacin derivative (Cip-OH) motif for antibacterial effect, and camptothecin (CPT) motif for chemotherapy). Using the designed molecule, a novel strategy of intracellular enzymatic nanofiber formation and synergistic antibacterium-enhanced chemotherapy and immunotherapy is achieved. Under endocytosis mediated by highly expressed biotin receptor in colorectal cancer cell membrane and the catalysis of highly expressed carboxylesterase in the cytoplasm, this novel molecule can be transformed into Biotin-Nap, which self-assembled into nanofibers. Meanwhile, antibiotic Cip-OH and chemotherapeutic drug CPT are released, overcoming bacterium-induced drug resistance and enhancing the therapeutic efficacy of immunotherapy towards colorectal cancer. This work offers a feasible strategy for the design of novel multifunctional prodrugs to improve the efficiency of colorectal cancer treatment.

Wheat silage partially replacing oaten hay exhibited greater feed efficiency and fibre digestion despite low feed intake by feedlot lambs.

This study aimed to investigate the feeding effect of wheat silage on growth performance, nutrient digestibility, rumen fermentation, and microbiota composition in feedlot lambs. Sixty-four male crossbred Chinese Han lambs (BW = 27.8 ± 0.67 kg, 3 months of age) were randomly assigned to four ration groups with wheat silage replacing 0% (WS0), 36% (WS36), 64% (WS64), and 100% (WS100) of oaten hay on forage dry matter basis. The concentrate-to-forage ratio was 80:20 and the feeding trial lasted 52 d. Increasing wheat silage inclusion linearly decreased dry matter intake by 4% to 27% (P < 0.01). However, increasing the wheat silage replacement of oaten hay by no more than 64% improved the feed efficiency by 14% as noted by the feed-to-gain ratio (P = 0.04). Apparent digestibility of organic matter (P < 0.01), neutral detergent fibre (P = 0.04) and acid detergent fibre (P < 0.01) quadratically increased. Ammonia nitrogen (P = 0.01) decreased while microbial protein production (P < 0.01) increased with the increase of wheat silage inclusion. Total volatile fatty acids concentration increased quadratically with the increase of wheat silage inclusion (P < 0.01), and the highest occurred in WS64. The molar proportion of acetate (P < 0.01) and acetate-to-propionate ratio (P = 0.04) decreased while butyrate (P < 0.01) and isovalerate (P = 0.04) increased. Increasing wheat silage inclusion increased the Firmicutes-to-Bacteroidota ratio by 226% to 357%, resulting in Firmicutes instead of Bacteroidota being the most abundant phylum. The relative abundance of cellulolytic Ruminococcus numerically increased but that of amylolytic Prevotella (P < 0.01) decreased as increasing wheat silage inclusion. Taken together, increasing wheat silage replacement of oaten hay by no more than 64% exhibited greater feed efficiency and fibre digestion despite low feed intake by feedlot lambs due to the change of Firmicutes-to-Bacteroidota ratio in the rumen.

Targeting and repolarizing M2-like tumor-associated macrophage-mediated MR imaging and tumor immunotherapy by biomimetic nanoparticles.

Anti-tumor M1-like and pro-tumor M2-like tumor-associated macrophages (TAMs) coexist in tumor microenvironments (TME). The adverse effects of these M1/M2 subsets on tumors directly affect the current strategies to improve anti-tumor immune response. Therefore, it has attracted great attention to change the tumor immunosuppressive microenvironment by reprogramming TAMs. In this paper, we constructed biomimetic nanoparticles (HMMDN-Met@PM) targeting M2-like TAMs for macrophage re-polarization. In detail, the core of the biomimetic nanoparticles is metformin-loaded hollow mesoporous manganese dioxide nanoparticles (HMMDN-Met). Benefited from the hollow and porous structure of HMMDN, metformin, the regulator of M1/M2 adopted in this work, can be easily and widely loaded into HMMDN. Moreover, macrophage membranes were utilized for HMMDN-Met coating (HMMDN-Met@MM) to prevent the premature drug leakage and provide specific molecular recognition/TME targeting. In addition, M2 macrophage targeting peptide (M2pep) was modified on the surface of macrophage membrane to specifically deliver the drug to M2-like TAMs to promote the polarization of M2 to M1 macrophages. Through in vitro and in vivo studies, we found that the expression of surface markers and inflammatory factors CD206, Arg-1 and IL-10 of type M2 macrophages decreased, while the surface markers of type M1 macrophages and the expression of inflammatory factors CD80, TNF-α and iNOS increased, indicating the successful re-polarization of M2 macrophages and finally realizing the inhibition of tumor growth. At the same time, under the acidic and GSH conditions of tumor, HMMDN was decomposed into Mn2+, which is a contrast agent for magnetic resonance imaging, thus realizing the tracking of tumor. This work practices biomimetic nanosystem in targeted imaging and immunotherapy, paving the way for strategy designing for tumor inhibition.

Dietary Guanidine Acetic Acid Addition Improved Carcass Quality with Less Back-Fat Thickness and Remarkably Increased Meat Protein Deposition in Rapid-Growing Lambs Fed Different Forage Types.

The aim of this study was to investigate whether guanidine acetic acid (GAA) yields a response in rapid-growing lambs depending on forage type. In this study, seventy-two small-tailed Han lambs (initial body weights = 12 ± 1.6 kg) were used in a 120-d feeding experiment after a 7-d adaptation period. A 2 × 3 factorial experimental feeding design was applied to the lambs, which were fed a total mixed ration with two forage types (OH: oaten hay; OHWS: oaten hay plus wheat silage) and three forms of additional GAA (GAA: 0 g/kg; UGAA: Uncoated GAA, 1 g/kg; CGAA: Coated GAA, 1 g/kg). The OH diet had a greater dry matter intake, average daily gain, and hot carcass weight than the OHWS diet. The GAA supplementation increased the final body weight, hot carcass weight, dressing percentage, and ribeye area in the longissimus lumborum. Meanwhile, it decreased backfat thickness and serum triglycerides. Dietary GAA decreased the acidity of the meat and elevated the water-holding capacity in mutton. In addition, the crude protein content in mutton increased with GAA addition. Dietary GAA (UGAA or CGAA) might be an effective additive in lamb fed by different forage types, as it has potential to improve growth performance and meat quality.

In situ generation of micrometer-sized tumor cell-derived vesicles as autologous cancer vaccines for boosting systemic immune responses.

Cancer vaccine, which can promote tumor-specific immunostimulation, is one of the most important immunotherapeutic strategies and holds tremendous potential for cancer treatment/prevention. Here, we prepare a series of nanoparticles composed of doxorubicin- and tyrosine kinase inhibitor-loaded and hyaluronic acid-coated dendritic polymers (termed HDDT nanoparticles) and find that the HDDT nanoparticles can convert various cancer cells to micrometer-sized vesicles (1.6-3.2 µm; termed HMVs) with ~100% cell-to-HMV conversion efficiency. We confirm in two tumor-bearing mouse models that the nanoparticles can restrain tumor growth, induce robust immunogenic cell death, and convert the primary tumor into an antigen depot by producing HMVs in situ to serve as personalized vaccines for cancer immunotherapy. Furthermore, the HDDT-healed mice show a strong immune memory effect and the HDDT treatment can realize long-term protection against tumor rechallenge. Collectively, the present work provides a general strategy for the preparation of tumor-associated antigen-containing vesicles and the development of personalized cancer vaccines.

Guanidine acetic acid exhibited greater growth performance in younger (13-30 kg) than in older (30-50 kg) lambs under high-concentrate feedlotting pattern.

Guanidine acetic acid (GAA) is increasingly considered as a nutritional growth promoter in monogastric animals. Whether or not such response would exist in rapid-growing lambs is unclear yet. The objective of this study was to investigate whether dietary supplementation with uncoated GAA (UGAA) and coated GAA (CGAA) could alter growth performance, nutrient digestion, serum metabolites, and antioxidant capacity in lambs. Seventy-two small-tailed Han lambs initially weighed 12 ± 1.6 kg were randomly allocated into six groups in a 2 × 3 factorial experimental design including two forage-type rations [Oaten hay (OH) vs. its combination with wheat silage (OHWS)] and three GAA treatment per ration: no GAA, 1 g UGAA, and 1 g CGAA per kg dry matter. The whole experiment was completed in two consecutive growing stages (stage 1, 13-30 kg; stage 2, 30-50 kg). Under high-concentrate feeding pattern (Stage 1, 25: 75; Stage 2, 20: 80), UGAA or CGAA supplementation in young lambs presented greater dry matter intake (DMI) in stage 1 and average daily gain (ADG) in the whole experimental period; lambs in OH group had higher ADG and DMI than that in OHWS group in stage 1 and whole experimental period, but this phenomenon was not observed in stage 2. Both UCGA and CGAA addition increased dietary DM, organic matter (OM), neutral detergent fiber (NDF), and acid detergent fiber (ADF) digestion in both stages. In blood metabolism, UCGA and CGAA addition resulted in a greater total protein (TP) and insulin-like growth factor 1(IGF-1) levels, as well as antioxidant capacity; at the same time, UCGA and CGAA addition increased GAA metabolism-creatine kinase and decreased guanidinoacetate N-methyltransferase (GAMT) and L-Arginine glycine amidine transferase catalyzes (AGAT) activity. In a brief, the results obtained in the present study suggested that GAA (UGAA and CGAA; 1 g/kg DM) could be applied to improve growth performance in younger (13-30 kg) instead of older (30-50 kg) lambs in high-concentrate feedlotting practice.

Lipid droplet-hitchhiking probe creates Trojan foam cells for fluorescence/photoacoustic imaging of atherosclerotic plaques.

Since atherosclerosis, a disease characterized by abnormal arterial lipid deposition, may lead to fatal cardiovascular diseases, imaging of atherosclerotic plaques is of great value for their pathological assessment. In this study, we propose a lipid droplet (LD)-hitchhiking strategy to in situ create Trojan foam cells for fluorescence/photoacoustic imaging of atherosclerotic plaques via homologous targeting effect. In our design, functional liposomes (DCP liposomes) composed of phospholipid dioleoylphosphatidylserine (DOPS), a novel LD inducer we found, and Cypate-PC, a synthesized lipid-like molecular probe, have demonstrated great capability of inducing LDs in monocytes/macrophages while being enveloped into the resulting Trojan foam cells. Taking advantage of homologous targeting effect, the imaging probe hitchhikes on the LDs in Trojan foam cells for targeted transport to the plaque sites. Moreover, the confinement in highly hydrophobic LDs endows the imaging probe with high efficiency in light absorption, enabling greatly intensified fluorescence/photoacoustic signals. The DCP liposomes have shown great potency in inducing the generation of Trojan foam cells, and eventually ex vivo fluorescence imaging and in vivo photoacoustic imaging of atherosclerotic plaques. The proposed strategy provides more insights into the design of targeted imaging methodologies, and also an effective avenue to facilitate the evaluation and subsequent treatment of atherosclerotic plaques.

Trident Molecule with Nanobrush-Nanoparticle-Nanofiber Transition Property Spatially Suppresses Tumor Metastasis.

Metastasis-induced high mortality of cancers urgently demands new approaches to simultaneously inhibit primary tumor metastasis and distant tumor growth. Herein, by rational design of a trident molecule Nap-Phe-Phe-Lys(SA-CPT)-Lys(SA-HCQ)-Tyr(H2PO3)-OH (Nap-CPT-HCQ-Yp) with three functional "spears" (i.e., a phosphotyrosine motif for enzymatic self-assembly, camptothecin (CPT) motif for chemotherapy, and hydroxychloroquine (HCQ) motif for autophagy inhibition) and nanobrush-nanoparticle-nanofiber transition property, we propose a novel strategy of intracellular enzymatic nanofiber formation and synergistic autophagy inhibition-enhanced chemotherapy and immunotherapy for spatial suppression of tumor metastasis. Under sequential alkaline phosphatase catalysis and carboxylesterase hydrolysis, Nap-CPT-HCQ-Yp undergoes nanobrush-nanoparticle-nanofiber transition, accompanied by the releases of CPT and HCQ. The formed intracellular nanofibers effectively inhibit the metastasis and invasion behaviors of cancer cells. Meanwhile, the released CPT and HCQ synergistically induce a prominent therapeutic effect through autophagy inhibition-enhanced chemotherapy. Furthermore, chemotherapy of Nap-CPT-HCQ-Yp enhances immunogenic cell death, resulting in the activation of toxic T-cells. Finally, a combination of checkpoint blockade therapy and Nap-CPT-HCQ-Yp-mediated chemotherapy elicits systemic antitumor immunity, thereby achieving efficient inhibitions of primary tumors as well as distant tumors in a breast tumor model. Our work offers a simple and feasible strategy for the design of "smart" multifunctional prodrugs to spatially suppress tumor metastasis.

Rose Bengal-Derived Ultrabright Sulfur-Doped Carbon Dots for Fast Discrimination between Live and Dead Cells.

The discrimination between dead and live cells is crucial for cell viability evaluation. Carbon dots (CDs), with advantages like simple and cost-effective synthesis, excellent biocompatibility, and high photostability, have shown potential for realizing selective live/dead cell staining. However, most of the developed CDs with the live/dead cell discrimination capacity usually have low photoluminescence quantum yields (PLQYs) and excitation wavelength-dependent fluorescence emission (which can cause fluorescence overlap with other fluorescent probes and make dual-color live/dead staining impossible), and hence, developing ultrabright CDs with excitation wavelength-independent fluorescence emission property for live/dead cell discrimination becomes an important task. Here, using a one-pot hydrothermal method, we prepared ultrasmall (∼1.6 nm), ultrabright (PLQY: ∼78%), and excitation wavelength-independent sulfur-doped carbon dots (termed S-CDs) using rose bengal and 1,4-dimercaptobenzene as raw materials and demonstrated that the S-CDs could rapidly (∼5 min) and accurately distinguish dead cells from live ones for almost all the cell types including bacterial, fungal, and animal cells in a wash-free manner. We confirmed that the S-CDs could rapidly pass through the dead cell surfaces to enter the interior of the dead cells, thus visualizing these dead cells. In contrast, the S-CDs could not enter the interior of live cells and thus could not stain these live cells. We further verified that the S-CDs presented better biocompatibility and higher photostability than the commercial live/dead staining dye propidium iodide, ensuring its bright application prospect in cell imaging and cell viability assessment. Overall, this work develops a type of CDs capable of realizing the live/dead cell discrimination of almost all the cell types (bacterial, fungal, and animal cells), which has seldom been achieved by other fluorescent nanoprobes.

Photostable AIE probes for wash-free, ultrafast, and high-quality plasma membrane staining.

Plasma membrane (PM), a fundamental building component of a cell, is responsible for a variety of cell functions and biological processes. However, it is still challenging to acquire its morphology and morphological variation information via an effective approach. Herein, we report a PM imaging study regarding an aggregation-induced emission luminogen (AIEgen) called tetraphenylethylene-naphthalimide+ (TPE-NIM+), which is derived from our previously reported tetraphenylethylene-naphthalimide (TPE-NIM). The designed AIEgen (TPE-NIM+) shows significant characteristics of ultrafast staining, high photostability, wash-free property, and long retention time at the PM, which can structurally be correlated with its positively charged quaternary amine and hydrophobic moiety. TPE-NIM+ is further applied for staining of different cell lines, proving its universal PM imaging capability. Most importantly, we demonstrate that TPE-NIM+ can clearly delineate the contours of densely packed living cells with high cytocompatibility. Therefore, TPE-NIM+ as a PM imaging reagent superior to currently available commercial PM dyes shall find a number of applications in the biological/biomedical fields and even beyond.

Palladium Nanosheets as Safe Radiosensitizers for Radiotherapy.

Many noble metal-based nanoparticles have emerged for applications in cancer radiotherapy in recent years, but few investigations have been carried out for palladium nanoparticles. Herein, palladium nanosheets (Pd NSs), which possess a sheetlike morphology with a diameter of ∼14 nm and a thickness of ∼2 nm, were utilized as a sensitizer to improve the performance of radiotherapy. It was found that Pd NSs alone did not decrease the cell viability after treatment for as long as 130 h, suggesting the excellent cytocompatibility of the nanoagents. However, the viability of cancer cells treated with X-ray irradiation became lower, and the viability became even lower if the cells were co-treated with X-ray and Pd NSs, indicating the radiosensitization effect of Pd NSs. Additionally, compared with X-ray irradiation, the combined treatment of Pd NSs and X-ray irradiation induced the generation of more DNA double-stranded breaks and reactive oxygen species within cancer cells, which eventually caused elevated cell apoptosis. Moreover, in vivo experiments also verified the radiosensitization effect and the favorable biocompatibility of Pd NSs, indicating their potential for acquiring satisfactory in vivo radiotherapeutic effect at lower X-ray doses. It is believed that the present research will open new avenues for the application of noble metal-based nanoparticles in radiosensitization.

Endosome/lysosome-detained supramolecular nanogels as an efflux retarder and autophagy inhibitor for repeated photodynamic therapy of multidrug-resistant cancer.

The presence of drug efflux pumps and endo/lysosomal entrapment phenomena in multidrug-resistant cancer cells leads to insufficient and off-target accumulation of anticancer drugs in the cells, which severely reduces the drugs' therapeutic efficacies. Here, we prepare a novel type of photosensitizer (PS)-loaded supramolecular nanogel, which can utilize the endo/lysosomal entrapment for enhanced photodynamic therapy (PDT) of multidrug-resistant cancer. The PS-loaded nanogels can elude the drug efflux pumps, and be markedly internalized by drug-resistant cancer cells through the endocytic pathway. With their pH-sensitive properties, the internalized nanogels can aggregate in the acidic endosomes/lysosomes, thus retarding their exocytosis from the cells. Moreover, the lysosomes of the nanogel-treated cells are severely damaged after irradiation, which inhibits the protective autophagy and improves the photodynamic therapeutic performance of the nanogels. Besides, the in vivo experiments show that the nanogels significantly prolong the tumor retention of the PSs, thus enabling multiple PDT treatments after a single drug injection.

Mitochondria-acting nanomicelles for destruction of cancer cells via excessive mitophagy/autophagy-driven lethal energy depletion and phototherapy.

Mitophagy is a specific self-protective autophagic process that degrades damaged or dysfunctional mitochondria, and is generally considered to reduce the effectiveness of mitochondria-targeted therapies. Here, we report an energy depletion-based anticancer strategy by selectively activating excessive mitophagy in cancer cells. We fabricate a type of mitochondria-targeting nanomicelles via the self-assembly of D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and dc-IR825 (a near-infrared cyanine dye and a photothermal agent). The TPGS/dc-IR825 nanomicelles enable mitochondrial damage in cancer cells, which, for self-protection, activate two autophagic pathways, (1) mitophagy and (2) adenosine triphosphate (ATP) shortage-triggered autophagy. However, the excessive mitophagy/autophagy activities far surpass the degradative capacity of autolysosomes, leading to the formation of micrometer-sized vacuoles and degradation blockage. Immunofluorescence staining and Western blot analysis reveal that the nanomicelle-treated cancer cells are under severe ATP shortage, which eventually causes substantial cell death. Moreover, the nanomicelles intravenously injected into tumor-bearing mice show high tumor accumulation, long tumor retention, and inhibit the tumor growth by inducing excessive mitophagy/autophagy and energy depletion in tumor cells. Additional near-infrared laser irradiation treatment further enhances the in vitro and in vivo anticancer efficiencies of the nanomicelles, due to the excellent photothermal and photodynamic effects of dc-IR825. We believe that this work highlights the important role of mitophagy/autophagy in treating cancers.

Colistin-Loaded Polydopamine Nanospheres Uniformly Decorated with Silver Nanodots: A Nanohybrid Platform with Improved Antibacterial and Antibiofilm Performance.

Bacterial infections, especially chronic infections caused by bacterial biofilms, have become a worldwide threat to public health. Encouragingly, the synergistic actions of two or more antibacterial drugs have been proven to be effective in treating refractory bacterial infections. Herein, we fabricated a robust antibacterial nanohybrid, the colistin-loaded polydopamine nanospheres (PDA NSs) decorated uniformly with small silver nanodots (u-CPSs), and the u-CPSs could realize synergistic bactericidal performance for combating bacterial infections. PDA NSs, as an adhesive nanocarrier, could bind to the bacterial surfaces, where the drugs (colistin and silver ions) on the PDA surfaces could be released persistently via a near-infrared laser-triggered manner. Interestingly, compared with colistin-loaded PDA NSs decorated sparsely with large silver nanoparticles (s-CPSs), the u-CPSs exhibited stronger antibacterial and antibiofilm effects. We have also demonstrated that the u-CPSs could disrupt the cell walls/membranes of Gram-negative Escherichia coli bacteria and induce the generation of toxic reactive oxygen species within the bacteria. Collectively, the present work exemplifies the exquisite design and synthesis of PDA-based nanohybrids for achieving synergistic antibacterial and antibiofilm activities, which may promote the development of more powerful nanoagents to fight against bacterial infections.

Palladium nanosheet-knotted injectable hydrogels formed via palladium-sulfur bonding for synergistic chemo-photothermal therapy.

Nanoparticle (NP)-based hydrogels that can introduce synergistic advantages to the novel three-dimensional scaffold have garnered much attention recently. However, the application of NP-crosslinked hydrogels still remains challenging due to the complicated synthesis and/or modification of the NPs and the changed properties of the NPs after gelation. Herein, a novel palladium nanosheet (Pd NS)-based hydrogel (Pd Gel) with Pd NSs as crosslinkers was obtained by simply mixing Pd NSs with thiol-terminated four-arm polyethylene glycol (4arm-PEG-thiol). It was found that the formed Pd Gel was injectable, possibly due to the dynamic Pd-S bonds formed between Pd NSs and 4arm-PEG-thiol. In addition, compared with free Pd NSs, the Pd NSs within the hydrogel exhibited a significantly higher stability. We have further demonstrated that the formed hydrogel could encapsulate the commonly used anticancer drug doxorubicin (DOX) to form DOX@Pd Gel for combined chemo-photothermal therapy. Particularly, Pd NSs with a high absorption in the near-infrared (NIR) region could convert the energy of NIR laser into heat with a high efficiency, which is beneficial for photothermal therapy. Moreover, DOX@Pd Gel could maintain a sustainable release of DOX and the NIR laser irradiation could accelerate this drug release process. Then, the explosively released DOX and the hyperthermia generated from Pd NSs under NIR laser irradiation acted in a synergistic way to realize the combined therapeutic effect of the chemo-photothermal treatment. Finally, the in vivo anticancer effect and safety of the combined therapy were also verified by the tumor-bearing mouse model. Taken together, this work constructs a NP-crosslinked, NIR laser-activatable and injectable photothermal hydrogel via dynamic Pd-S bonding, and demonstrates that the hydrogel allows us to release DOX more precisely, eliminate tumor more effectively and inhibit tumor metastasis more persistently, which will advance the development of novel anticancer strategies.

From perinuclear to intranuclear localization: A cell-penetrating peptide modification strategy to modulate cancer cell migration under mild laser irradiation and improve photothermal therapeutic performance.

Tumor metastasis is a key cause that leads to the failure of cancer treatment. Inhibition of metastasis, rather than the simple removal of the primary tumor, is critical to the survival improvement. Here, we report a cell-penetrating peptide-modification strategy to realize substantial perinuclear accumulation and subsequent near-infrared (NIR) laser-triggered nuclear entry of palladium nanosheets (Pd NSs) for inhibition of cancer cell metastasis and photothermal cancer therapy. Specifically, it was found that the cell-penetrating peptide TAT-modified Pd NSs (abbreviated as Pd-TAT) mainly accumulated in the perinuclear region and showed the enhanced endocytosis and reduced efflux compared with the counterpart without TAT modification. On the one hand, Pd-TAT could inhibit cell migration and invasion. It was proposed that Pd-TAT located in the perinuclear region could promote the overexpression of lamin A/C proteins (related with nuclear stiffness) and increase the mechanical stiffness of the nucleus. More importantly, the introduction of NIR laser irradiation with a laser density of 0.3 W/cm2 (below the permitted value 0.329 W/cm2 for skin exposure) significantly enhanced the inhibitory effect of Pd-TAT on cancer cell migration, which might be due to the increased nuclear stiffness caused by the enhanced nuclear entry of Pd-TAT under the effect of mild laser-induced local hyperthermia in the perinuclear region. On the other hand, the increased nuclear entry of Pd-TAT under NIR laser irradiation greatly enhanced their photothermal therapeutic efficacy due to the susceptibility of the nucleus to hyperthermia. Taken together, the Pd-TAT-based and laser-promoted perinuclear-to-intranuclear localization strategy allows us to not only destroy the primary tumor more effectively, but also inhibit cancer metastasis more persistently.