OX40L-expressing M1-like macrophage exosomes for cancer immunotherapy.

With only limited clinical patient benefit, focusing on new immune checkpoint pathways could be an important complement to current immune checkpoint drugs. In addition, not only does T cell-mediated adaptive immunity play an important role, but also macrophage-mediated innate immunity, due to its abundant presence in solid tumors. Here, we developed an engineered M1-like macrophage exosome, OX40L M1-exos. OX40L M1-exos can activate the adaptive immunity by activating the OX40/OX40L pathway and can reprogram M2-like tumor-associated macrophages into M1-like macrophages, thereby restoring and enhancing macrophage-mediated innate immunity. Our OX40L M1-exos achieved an effective synergistic effect of innate and adaptive immunity and achieved a potent therapeutic effect in a mouse breast cancer model, effectively inhibiting tumor growth and metastasis. These results suggest that OX40L M1-exos are an attractive therapeutic strategy and may be an important complement to current cancer immunotherapies.

Biofilm microenvironment triggered self-enhancing photodynamic immunomodulatory microneedle for diabetic wound therapy.

The treatment of diabetic wounds faces enormous challenges due to complex wound environments, such as infected biofilms, excessive inflammation, and impaired angiogenesis. The critical role of the microenvironment in the chronic diabetic wounds has not been addressed for therapeutic development. Herein, we develop a microneedle (MN) bandage functionalized with dopamine-coated hybrid nanoparticles containing selenium and chlorin e6 (SeC@PA), which is capable of the dual-directional regulation of reactive species (RS) generation, including reactive oxygen species (ROS) and reactive nitrogen species (RNS), in response to the wound microenvironment. The SeC@PA MN bandage can disrupt barriers in wound coverings for efficient SeC@PA delivery. SeC@PA not only depletes endogenous glutathione (GSH) to enhance the anti-biofilm effect of RS, but also degrades GSH in biofilms through cascade reactions to generate more lethal RS for biofilm eradication. SeC@PA acts as an RS scavenger in wound beds with low GSH levels, exerting an anti-inflammatory effect. SeC@PA also promotes the M2-phenotype polarization of macrophages, accelerating wound healing. This self-enhanced, catabolic and dynamic therapy, activated by the wound microenvironment, provides an approach for treating chronic wounds.

NIR-dye bridged human serum albumin reassemblies for effective photothermal therapy of tumor.

Human serum albumin (HSA) based drug delivery platforms that feature desirable biocompatibility and pharmacokinetic property are rapidly developed for tumor-targeted drug delivery. Even though various HSA-based platforms have been established, it is still of great significance to develop more efficient preparation technology to broaden the therapeutic applications of HSA-based nano-carriers. Here we report a bridging strategy that unfastens HSA to polypeptide chains and subsequently crosslinks these chains by a bridge-like molecule (BPY-Mal2) to afford the HSA reassemblies formulation (BPY@HSA) with enhanced loading capacity, endowing the BPY@HSA with uniformed size, high photothermal efficacy, and favorable therapeutic features. Both in vitro and in vivo studies demonstrate that the BPY@HSA presents higher delivery efficacy and more prominent photothermal therapeutic performance than that of the conventionally prepared formulation. The feasibility in preparation, stability, high photothermal conversion efficacy, and biocompatibility of BPY@HSA may facilitate it as an efficient photothermal agents (PTAs) for tumor photothermal therapy (PTT). This work provides a facile strategy to enhance the loading capacity of HSA-based crosslinking platforms in order to improve delivery efficacy and therapeutic effect.

Dextran-based micelles for combinational chemo-photodynamic therapy of tumors via in vivo chemiluminescence.

Natural polysaccharides, represented by dextran, chitosan, and hyaluronic acid, are widely approved for use as pharmaceutical excipients and are important carrier materials for the design of advanced drug delivery systems, particularly in the field of anticancer drug delivery. The combination of stimuli-activable prodrug based chemotherapy and photodynamic therapy (PDT) has attracted increasing attention. Recent studies have verified the effectiveness of this strategy in the treatment of multiple aggressive cancers. However, in such combination, the stimuli-responsive chemotherapy and PDT have their own problems that need to be overcome. The uneven distribution of endogenous stimuli within tumor tissues makes it difficult for prodrug to be completely activated. And the inadequate tissue penetration depth of external light results in low efficiency of PDT. Aiming at these two bottlenecks, we designed a biocompatible dextran based - multi-component nanomedicine (PCL-NPs) that integrate a chemiluminescence agent luminol, a photosensitizer chlorine e6 (Ce6), and a reactive oxygen species (ROS)-activable thioketal-based paclitaxel (PTX) prodrug. The presence of overexpressed hydrogen peroxide (H2O2) inside tumor oxidizes the luminol moiety to generate in-situ light for PDT through chemiluminescence resonance energy transfer (CRET). The singlet oxygen (1O2) produced in this process not only directly kills tumor cells but also amplifies oxidative stress to accelerate the activation of PTX prodrug. We propose that the PCL-NPs have great therapeutic potential by simultaneously enhancing chemotherapy and PDT in a combination therapy.

Cucurbit[8]uril-based water-dispersible assemblies with enhanced optoacoustic performance for multispectral optoacoustic imaging.

Organic small-molecule contrast agents have attracted considerable attention in the field of multispectral optoacoustic imaging, but their weak optoacoustic performance resulted from relatively low extinction coefficient and poor water solubility restrains their widespread applications. Herein, we address these limitations by constructing supramolecular assemblies based on cucurbit[8]uril (CB[8]). Two dixanthene-based chromophores (DXP and DXBTZ) are synthesized as the model guest compounds, and then included in CB[8] to prepare host-guest complexes. The obtained DXP-CB[8] and DXBTZ-CB[8] display red-shifted and increased absorption as well as decreased fluorescence, thereby leading to a substantial enhancement in optoacoustic performance. Biological application potential of DXBTZ-CB[8] is investigated after co-assembly with chondroitin sulfate A (CSA). Benefiting from the excellent optoacoustic property of DXBTZ-CB[8] and the CD44-targeting feature of CSA, the formulated DXBTZ-CB[8]/CSA can effectively detect and diagnose subcutaneous tumors, orthotopic bladder tumors, lymphatic metastasis of tumors and ischemia/reperfusion-induced acute kidney injury in mouse models with multispectral optoacoustic imaging.

Mussel-inspired "plug-and-play" hydrogel glue for postoperative tumor recurrence and wound infection inhibition.

Currently, clinical tumor resection is faced with two options: open and minimally invasive surgery. Open surgery is easy to completely remove the lesion but is prone to infection, while minimally invasive surgery recovers faster but may cause tumor recurrence. To fill the shortcomings of the two surgical modes and make the choice for tumor resection more effortlessly, we developed a postoperative black phosphorus-Ag nanocomposites-loaded dopamine-modified hyaluronic acid-Pluronic® F127 (BP-Ag@HA-DA-Plu) hydrogel implantation system that can prevent tumor recurrence and wound infection simultaneously. Experiments have shown that the hydrogel system combined with 808 nm near-infrared (NIR) irradiation has excellent anti-tumor, antibacterial, and wound healing abilities. Additionally, unlike existing surgical hydrogel products that require inconvenient in-situ cross-linking, the BP-Ag@HA-DA-Plu hydrogel system offers "plug-and-play" functionality during surgery due to its thermo-responsiveness, injectability, and adhesion, thereby greatly improving the efficiency of surgery.

Microbial synthesis of Prussian blue for potentiating checkpoint blockade immunotherapy.

Cancer immunotherapy is revolutionizing oncology. The marriage of nanotechnology and immunotherapy offers a great opportunity to amplify antitumor immune response in a safe and effective manner. Here, electrochemically active Shewanella oneidensis MR-1 can be applied to produce FDA-approved Prussian blue nanoparticles on a large-scale. We present a mitochondria-targeting nanoplatform, MiBaMc, which consists of Prussian blue decorated bacteria membrane fragments having further modifications with chlorin e6 and triphenylphosphine. We find that MiBaMc specifically targets mitochondria and induces amplified photo-damages and immunogenic cell death of tumor cells under light irradiation. The released tumor antigens subsequently promote the maturation of dendritic cells in tumor-draining lymph nodes, eliciting T cell-mediated immune response. In two tumor-bearing mouse models using female mice, MiBaMc triggered phototherapy synergizes with anti-PDL1 blocking antibody for enhanced tumor inhibition. Collectively, the present study demonstrates biological precipitation synthetic strategy of targeted nanoparticles holds great potential for the preparation of microbial membrane-based nanoplatforms to boost antitumor immunity.

Self-driven nanoprodrug platform with enhanced ferroptosis for synergistic photothermal-IDO immunotherapy.

Insufficient immune stimulation and stubborn immune resistance are the critical factors limiting tumor immunotherapy. Here, we report a multifunctional nanoprodrug platform with self-driven indoximod (IND) release and oxidative stress amplification. The aim is to awaken immune responses and block the indoleamine 2,3-dioxygenase (IDO) pathway through a combination of ferroptosis, photothermal therapy, and immunotherapy. This nanosystem improved the delivery efficiency of IND due to click chemistry linked ROS responsive prodrug and self-driven drug release. Meanwhile, the tactic of simultaneously increasing ROS and eliminating GSH amplified oxidative stress and strengthened ferroptosis, which further enhanced immunogenicity along with polydopamine-based photothermal therapy. IDO immunization combined with ferroptosis as well as photothermal therapy not only stimulated immune response, but also reversed immune suppression with enhanced immune memory. Therefore, primary tumor, distant tumor, and cancer metastasis were inhibited. This study provides a perspective on immunotherapeutics for cancer treatment.

An injectable hydrogel based on Bi2Se3 nanosheets and hyaluronic acid for chemo-photothermal synergistic therapy.

To resolve poor accumulation caused by systemic administration, injectable and responsive hydrogels are the prospective drug delivery systems for localized tumor treatment, owning to negligible invasiveness and accurate administration. Herein, an injectable hydrogel, based on dopamine (DA) crosslinked hyaluronic acid and Bi2Se3 nanosheets (NSs) loading with doxorubicin (DOX) coated with polydopamine (Bi2Se3-DOX@PDA), was developed for synergistic chem-photothermal cancer therapy. The ultrathin functional Bi2Se3-DOX@PDA NSs could be responsive to the weak acidic condition and photothermal effect under NIR laser irradiation, achieving controlled release of DOX. Moreover, nanocomposite hydrogel based on hyaluronic acid matrix could be precisely administrated through intratumoral injection since its injectability and self-healing capacity, remaining at injected sites for at least 12 days. Furthermore, the excellent therapeutics effect of Bi2Se3-DOX@PDA nanocomposite hydrogel was demonstrated on 4 T1 xenograft tumor with outstanding injectability and negligible systemic side-effect. In short, the construction of Bi2Se3-DOX@PDA nanocomposite hydrogel paves a prospective path for local treatment of cancers.

Engineered drug-loaded cellular membrane nanovesicles for efficient treatment of postsurgical cancer recurrence and metastasis.

Cancer recurrence and metastasis are still common causes of postsurgery death in patients with solid tumors, suggesting that additional consolidation therapeutic strategies are necessary. We have previously found that oxaliplatin (OXA) treatment causes further up-regulation of CD155, which is abundantly expressed in tumors for resulting in increased sensitivity of cancer to anti-CD155 therapy. Here, we report O-TPNVs, which are TIGIT-expressing cell membrane and platelet cell membrane fusion nanovesicles (TPNVs) loaded with OXA. Platelet-derived membrane components enable O-TPNVs to target postsurgery wounds and interact with circulating tumor cells (CTCs). OXA directly kills residual tumor cells and CTCs, induces immunogenic cell death, and activates the immune system. TPNVs bind to CD155 on tumor cells, block the CD155/TIGIT pathway, and restore CD8+ T cell activity. In vivo analyses reveal that O-TPNVs achieve synergistic chemotherapeutic and immunotherapeutic effects, effectively inhibiting the recurrence and metastasis of triple-negative breast cancer (4T1) after surgery.

Emerging Strategies in Stimuli-Responsive Prodrug Nanosystems for Cancer Therapy.

Prodrugs are chemically modified drug molecules that are inactive before administration. After administration, they are converted in situ to parent drugs and induce the mechanism of action. The development of prodrugs has upgraded conventional drug treatments in terms of bioavailability, targeting, and reduced side effects. Especially in cancer therapy, the application of prodrugs has achieved substantial therapeutic effects. From serendipitous discovery in the early stage to functional design with pertinence nowadays, the importance of prodrugs in drug design is self-evident. At present, studying stimuli-responsive activation mechanisms, regulating the stimuli intensity in vivo, and designing nanoscale prodrug formulations are the major strategies to promote the development of prodrugs. In this review, we provide an outlook of recent cutting-edge studies on stimuli-responsive prodrug nanosystems from these three aspects. We also discuss prospects and challenges in the future development of such prodrugs.

Self-Assembled Aza-Boron-Dipyrromethene for Ferroptosis-Boosted Sonodynamic Therapy.

The presence of apoptosis inhibition proteins renders the cancer cells resistant to apoptosis, severely compromising the antitumor efficacy of sonodynamic therapy (SDT). Here, an intelligent anticancer nanoplatform based on an Aza-boron-dipyrromethene dye (denoted as Aza-BDY) is elaborately established for ferroptosis augmented SDT through cysteine (Cys) starvation. After endocytosis by tumor cells, Aza-BDY serves as both a ferroptosis inducing agent and a sonosensitizer for tumor treatment. The specific Cys response facilitates the disruption of redox homeostasis and initiation of cellular ferroptosis. Meanwhile, the released sonosensitizer causes efficient SDT and augments ferroptosis under ultrasound irradiation. Detailed in vitro and in vivo investigations demonstrate that the synergistic effect of Cys depletion and singlet oxygen (1 O2 ) generation significantly induces cancer-cell death and suppresses tumor proliferation with a high inhibition rate of 97.5 %.

Mussel-Inspired Ligand Clicking and Ion Coordination on 2D Black Phosphorus for Cancer Multimodal Imaging and Therapy.

As a promising 2D nanocarrier, the biggest challenge of bare black phosphorus nanosheets (BP NSs) lies in the inherent instability, while it can be improved by surface modification strategies to a great extent. Considering the existing infirm BP NSs surface modification strategies, A mussels-inspired strong adhesive biomimetic peptide with azide groups for surface modification to increase the stability of BP NSs is synthesized. The azide groups on the peptide can quickly and precisely bind to the targeting ligand through click chemistry, solving the problem of nonspecificity of secondary modification of other mussel-mimicking materials. Besides, a catechol-Gd3+ coordination network is further constructed for magnetic resonance imaging (MRI) and inducing intracellular endo/lysosome escape. The fabricated BP-DOX@Gd/(DOPA)4 -PEG-TL nanoplatform exhibits enhanced antitumor abilities through synergetic chemo/photothermal effects both in vitro and in vivo.

Polyphenol-based hydrogels: Pyramid evolution from crosslinked structures to biomedical applications and the reverse design.

As a kind of nature-derived bioactive materials, polyphenol-based hydrogels possess many unique and outstanding properties such as adhesion, toughness, and self-healing due to their specific crosslinking structures, which have been widely used in biomedical fields including wound healing, antitumor, treatment of motor system injury, digestive system disease, oculopathy, and bioelectronics. In this review, starting with the classification of common polyphenol-based hydrogels, the pyramid evolution process of polyphenol-based hydrogels from crosslinking structures to derived properties and then to biomedical applications is elaborated, as well as the efficient reverse design considerations of polyphenol-based hydrogel systems are proposed. Finally, the existing problems and development prospects of these hydrogel materials are discussed. It is hoped that the unique perspective of the review can promote further innovation and breakthroughs of polyphenol-based hydrogels in the future.

Polymeric microneedle-mediated sustained release systems: Design strategies and promising applications for drug delivery.

Parenteral sustained release drug formulations, acting as preferable platforms for long-term exposure therapy, have been wildly used in clinical practice. However, most of these delivery systems must be given by hypodermic injection. Therefore, issues including needle-phobic, needle-stick injuries and inappropriate reuse of needles would hamper the further applications of these delivery platforms. Microneedles (MNs) as a potential alternative system for hypodermic needles can benefit from minimally invasive and self-administration. Recently, polymeric microneedle-mediated sustained release systems (MN@SRS) have opened up a new way for treatment of many diseases. Here, we reviewed the recent researches in MN@SRS for transdermal delivery, and summed up its typical design strategies and applications in various diseases therapy, particularly focusing on the applications in contraception, infection, cancer, diabetes, and subcutaneous disease. An overview of the present clinical translation difficulties and future outlook of MN@SRS was also provided.

pH-Sensitive and Charge-Reversal Polymeric Nanoplatform Enhanced Photothermal/Photodynamic Synergistic Therapy for Breast Cancer.

As reported, breast cancer is one of the most common malignancies in women and has overtaken lung cancer as the most commonly diagnosed cancer worldwide by 2020. Currently, phototherapy is a promising anti-tumor therapy due to its fewer side effects, less invasiveness, and lower cost. However, its application in cancer therapeutics is limited by the incomplete therapeutic effect caused by low drug penetration and monotherapy. Herein, we built a charge-reversal nanoplatform (Ce6-PLGA@PDA-PAH-DMMA NPs), including polydopamine (PDA) and chlorin e6 (Ce6) for enhancing photothermal/photodynamic synergistic therapy. The PAH-DMMA charge-reversal layer enabled Ce6-PLGA@PDA-PAH-DMMA NPs to have long blood circulation at the normal physiological environment and to successfully realize charge reversal under the weakly acidic tumor microenvironment, improving cellular uptake. Besides, in vitro tests demonstrated that Ce6-PLGA@PDA-PAH-DMMA NPs had high photothermal conversion and greater anti-tumor activity than no charge-reversal nanoparticles, which overcame the limited tumor therapeutic efficacy of PTT or photodynamic therapy alone. Overall, the design of pH-responsive and charge-reversal nanoparticles (Ce6-PLGA@PDA-PAH-DMMA NPs) provided a promising approach for synergistic PTT/PDT therapy against breast cancer.

N, S-Doped Carbon Dots Prepared by Peanut Protein Isolates and Cysteamine as Highly Sensitive Fluorescent Sensors for Fe2+, Fe3+ and Lactoferrin.

Lactoferrin (LF) is an iron-binding glycoprotein with various biological activities that has been extensively used in food and medical applications. Several methods for detecting LF have been reported, but they still face challenges in terms of sensitivity and simplicity of detection. To achieve an accurate and efficient detection of LF, we developed a method for the determination of LF in lactoferrin supplements using carbon dots (CDs) fluorescent probes. The N, S-doped PPI carbon dots (N, S-PPI-CDs) were prepared using a protein (peanut protein isolate) and cysteamine as precursors. The prepared N, S-PPI-CDs exhibited intense blue fluorescence and good biocompatibility, while the fluorescence intensity of the N, S-PPI-CDs showed a good linear relationship with Fe2+/Fe3+ concentration (0-2 µM). The N, S-PPI-CDs exhibited a high potential ability to rapidly detect Fe2+/Fe3+ within 30 s, with a limit of detection (LoD) of 0.21 µM/0.17 µM. Due to the reversible binding of LF to Fe, the N, S-PPI-CDs showed a high sensitivity and selectivity for LF, with a limit of detection (LoD) of 1.92 µg/mL. In addition, LF was quantified in real sample LF supplements and showed a fluctuation in recovery of less than 2.48%, further demonstrating the effectiveness of the fluorescent N, S-PPI-CDs sensor.

Charge-reversal biodegradable MSNs for tumor synergetic chemo/photothermal and visualized therapy.

Given the difficulties of biodegradation of mesoporous silica nanoparticles (NPs), enrichment and penetration of tumor sites, and real-time monitoring of the treatment process, we developed a kind of mannose-doping doxorubicin-loading mesoporous silica nanoparticle (MSN-Man-DOX) and coated by polydopamine-Gd3+ (PDAGd) metal-phenolic networks, as well as modified by poly (2-Ethyl-2-Oxazoline) (PEOz), constructing a novel nanomedicine MSN-Man-DOX@PDA-Gd-PEOz. Its pH-responsive charge reversal, photothermal, biodegradation, drug release, and magnetic resonance imaging (MRI) properties were evaluated in vitro. Cellular uptake, tumor penetration, lysosomal escape properties, as well as cell safety and toxicity of the nanoplatform were investigated through cell experiments. Finally, the MRI, organ distribution, photothermal condition, and comprehensive anti-tumor therapy in vivo were evaluated comprehensively through animal experiments. Research results showed that MSN-Man-DOX@PDA-Gd-PEOz had outstanding tumor enrichment and penetration abilities, which can produce excellent treatment effects through the synergistic effect of chemotherapy and photothermal therapy (PTT) with the function of magnetic resonance imaging contrast agent for disease monitoring. Besides, after finishing the therapeutic effect MSN-Man-DOX@PDA-Gd-PEOz can be biodegraded, so it had a good prospect of clinical application.

Self-assembled organic nanomedicine enables ultrastable photo-to-heat converting theranostics in the second near-infrared biowindow.

Development of organic theranostic agents that are active in the second near-infrared (NIR-II, 1000-1700 nm) biowindow is of vital significance for treating deep-seated tumors. However, studies on organic NIR-II absorbing agents for photo-to-heat energy-converting theranostics are still rare simply because of tedious synthetic routes to construct extended π systems in the NIR-II region. Herein, we design a convenient strategy to engineer highly stable organic NIR-II absorbing theranostic nanoparticles (Nano-BFF) for effective phototheranostic applications via co-assembling first NIR (NIR-I, 650-1000 nm) absorbing boron difluoride formazanate (BFF) dye with a biocompatible polymer, endowing the Nano-BFF with remarkable theranostic performance in the NIR-II region. In vitro and in vivo investigations validate that Nano-BFF can serve as an efficient theranostic agent to achieve photoacoustic imaging guided deep-tissue photonic hyperthermia in the NIR-II biowindow, achieving dramatic inhibition toward orthotopic hepatocellular carcinoma. This work thus provides an insight into the exploration of versatile organic NIR-II absorbing nanoparticles toward future practical applications.