Steerable Microneedles Enabling Deep Delivery of Photosensitizers and CRISPR/Cas9 Systems for Effective Combination Cancer Therapy.

Although gene therapy has shown prospects in treating triple-negative breast cancer, it is insufficient to treat such a malignant tumor. Herein, nanoparticles (NPs)-embedded dissolving microneedles (IR780-PL/pFBXO44@MNs) with steerable and flectional property were developed to achieve the codelivery of FBXO44-targeted CRISPR/Cas9 plasmids (pFBXO44) and hydrophobic photosensitizers. For improved NP penetration in tumor tissue, collagenase@MNs were preapplied to degrade the tumor matrix. Under light irradiation, IR780 exhibited remarkable phototherapy, while the escape efficiency of NPs from lysosomes was improved. pFBXO44 was subsequently released in tumor cell cytoplasm via reducing the disulfide bonds of NPs, which could specifically knock out the FBXO44 gene to inhibit the migration and invasion of tumor cells. As a result, tumor cells were eradicated, and lung metastasis was effectively suppressed. This micelle-incorporated microneedle platform broadens the potential of combining gene editing and photo synergistic cancer therapy.

Enhancing photodynamic immunotherapy by reprograming the immunosuppressive tumor microenvironment with hypoxia relief.

Tumor hypoxia impairs the generation of reactive oxygen species and the induction of immunogenic cell death (ICD) for photodynamic therapy (PDT), thus impeding its efficacy and the subsequent immunotherapy. In addition, hypoxia plays a critical role in forming immunosuppressive tumor microenvironments (TME) by regulating the infiltration of immunosuppressive tumor-associated macrophages (TAMs) and the expression of programmed death ligand 1 (PD-L1). To simultaneously tackle these issues, a MnO2-containing albumin nanoplatform co-delivering IR780, NLG919, and a paclitaxel (PTX) dimer is designed to boost photodynamic immunotherapy. The MnO2-catalyzed oxygen supply bolsters the efficacy of PDT and PTX-mediated chemotherapy, collectively amplifying the induction of ICD and the expansion of tumor-specific cytotoxic T lymphocytes (CTLs). More importantly, hypoxia releif reshapes the immunosuppressive TME via down-regulating the intratumoral infiltration of M2-type TAMs and the PD-L1 expression of tumor cells to enhance the infiltration and efficacy of CTLs in combination with immune checkpoint blockade (ICB) by NLG919, consequently eradicating primary tumors and almost completely preventing tumor relapse and metastasis. This study sets an example of enhanced immunotherapy for breast cancers through dual ICD induction and simultaneous immunosuppression modulation via both hypoxia relief and ICB, providing a strategy for the treatment of other hypoxic and immunosuppressive cancers.

Exceptional Strength-Ductility Combinations of a CoCrNi-Based Medium-Entropy Alloy via Short/Medium-Time Annealing after Hot-Rolling.

Strong yet ductile alloys have long been desired for industrial applications to enhance structural reliability. This work produced two (CoCrNi)93.5Al3Ti3C0.5 medium-entropy alloys with exceptional strength-ductility combinations, via short/medium (3 min/30 min) annealing times after hot-rolling. Three types of intergranular precipitates including MC, M23C6 carbides, and L12 phase were detected in both samples. Noticeably, the high-density of intragranular L12 precipitates were only found in the medium-time annealed sample. Upon inspection of the deformed substructure, it was revealed that the plane slip is the dominant deformation mechanism of both alloys. This is related to the lower stacking fault energy, higher lattice friction induced by the C solute, and slip-plane softening caused by intragranular dense L12 precipitates. Additionally, we noted that the stacking fault and twinning act as the mediated mechanisms in deformation of the short-time annealed alloy, while only the former mechanism was apparent in the medium-time annealed alloy. The inhibited twinning tendency can be attributed to the higher energy stacking faults and the increased critical twinning stress caused by intragranular dense L12 precipitates. Our present findings provide not only guidance for optimizing the mechanical properties of high/medium-entropy alloys, but also a fundamental understanding of deformation mechanisms.

Recent applications of phase-change materials in tumor therapy and theranostics.

Phase-change materials (PCMs) are a type of special material which can store and release a large amount of thermal energy without any significant temperature change. They are emerging in recent years as a promising functional material in tumor therapy and theranostics due to their accurate responses to the temperature variations, biocompatibility and low toxicity. In this review, we will introduce the main types of PCMs and their desirable physiochemical properties for biomedical applications, and highlight the recent progress of PCM's applications in the modulated release of antitumor drugs, with special attentions paid to various ways to initiate temperature-dependent phase change, the concomitant thermal therapy and its combination with or activation of other therapies, particularly unconventional therapies. We will also summarize PCM's recent applications in tumor theranostics, where both drugs and imaging probes are delivered by PCMs for controlled drug release and imaging-guided therapy. Finally, the future perspectives and potential limitations of harnessing PCMs in tumor therapy will be discussed.

Controllable hypoxia-activated chemotherapy as a dual enhancer for synergistic cancer photodynamic immunotherapy.

The efficacy of photodynamic therapy (PDT) is severely limited by the hypoxic tumor microenvironment (TME), while the performance of PDT-aroused antitumor immunity is frustrated by the immunosuppressive TME and deficient immunogenic cell death (ICD) induction. To simultaneously tackle these pivotal problems, we herein create an albumin-based nanoplatform co-delivering IR780, NLG919 dimer and a hypoxia-activated prodrug tirapazamine (TPZ) as the dual enhancer for synergistic cancer therapy. Under NIR irradiation, IR780 generates 1O2 for PDT, which simultaneously cleaves the ROS-sensitive linker for triggered TPZ release, and activates its chemotherapy via exacerbated tumor hypoxia. Meanwhile, firstly found by us, TPZ-mediated chemotherapy boosts PDT-induced tumor ICD to evoke stronger antitumor immunity including the development of tumor-specific cytotoxic T lymphocytes (CTLs). Eventually, enriched intratumoral GSH triggers the activation of NLG919 to mitigate the immunosuppressive TME via specific indoleamine 2,3-dioxygenase 1 (IDO-1) inhibition, consequently promoting the intratumoral infiltration of CTLs and the killing of both primary and distant tumors, while the resultant memory T cells allows nearly 100% suppression of tumor recurrence and metastasis. This nanoplatform sets up an example for dully enhanced photodynamic immunotherapy of breast cancer via hypoxia-activated chemotherapy, and paves a solid way for the treatment of other hypoxic and immunosuppressive malignant tumors.

Recent Advances of Tumor Microenvironment-Responsive Nanomedicines-Energized Combined Phototherapy of Cancers.

Photodynamic therapy (PDT) has emerged as a powerful tumor treatment tool due to its advantages including minimal invasiveness, high selectivity and thus dampened side effects. On the other side, the efficacy of PDT is severely frustrated by the limited oxygen level in tumors, thus promoting its combination with other therapies, particularly photothermal therapy (PTT) for bolstered tumor treatment outcomes. Meanwhile, nanomedicines that could respond to various stimuli in the tumor microenvironment (TME) provide tremendous benefits for combined phototherapy with efficient hypoxia relief, tailorable drug release and activation, improved cellular uptake and intratumoral penetration of nanocarriers, etc. In this review, we will introduce the merits of combining PTT with PDT, summarize the recent important progress of combined phototherapies and their combinations with the dominant tumor treatment regimen, chemotherapy based on smart nanomedicines sensitive to various TME stimuli with a focus on their sophisticated designs, and discuss the challenges and future developments of nanomedicine-mediated combined phototherapies.

Microstructure and Mechanical Properties of a Medium-Mn Steel with 1.3 GPa-Strength and 40%-Ductility.

Steel designs with superior mechanical properties have been urgently needed in automotive industries to achieve energy conservation, increase safety, and decrease weight. In this study, the aging process is employed to enhance the yield strength (YS) by tailoring the distribution of V-rich precipitates and to improve ductility by producing high volume fractions of recrystallized ferrite in cold-rolled medium-Mn steel. A reliable method to acquire ultra-high strength (1.0-1.5 GPa), together with ductility (>40%), is proposed via utilizing non-recrystallized austenite and recrystallized ferrite. Similarly to conventional medium-Mn steels, the TRIP effect, along with the mild TWIP effect, is responsible for the main deformation mechanisms during tensile testing. However, the coupled influence of precipitation strengthening, grain refinement strengthening, and dislocation strengthening contributes to an increase in YS. The studied steel, aged at 650 °C for 5 h, demonstrates a YS of 1078 MPa, ultimate tensile strength (UTS) of 1438 MPa, and tensile elongation (TE) of 30%. The studied steel aged at 650 °C for 10 h shows a UTS of 1306 MPa and TE of 42%, resulting in the best product in terms of of UTS and TE, at 55 GPa·%. Such a value surpasses that of the previously reported medium-Mn steels containing equal mass fractions of various microalloying elements.