A Programmable Microfluidic Paper-Based Analytical Device for Simultaneous Colorimetric and Photothermal Visual Sensing of Multiple Enzyme Activities.

New strategies for the simultaneous and portable detection of multiple enzyme activities are highly desirable for clinical diagnosis and home care. However, the methods developed thus far generally suffer from high costs, cumbersome procedures, and heavy reliance on large-scale instruments. To satisfy the actual requirements of rapid, accurate, and on-site detection of multiple enzyme activities, we report herein a smartphone-assisted programmable microfluidic paper-based analytical device (µPAD) that utilizes colorimetric and photothermal signals for simultaneous, accurate, and visual quantitative detection of alkaline phosphatase (ALP) and butyrylcholinesterase (BChE). Specifically, the operation of this µPAD sensing platform is based on two sequential steps. Cobalt-doped mesoporous cerium oxide (Co-m-CeO2) with remarkable peroxidase-like activities under neutral conditions first catalytically decomposes H2O2 for effectively converting colorless 3,3',5,5'-tetramethylbenzidine (TMB) into blue oxidized TMB (oxTMB). The subsequent addition of ALP or BChE to their respective substrates produces a reducing substance that can somewhat inhibit the oxTMB transformation for compromised colorimetric and photothermal signals of oxTMB. Notably, these two-step bioenzyme-nanozyme cascade reactions strongly support the straightforward and excellent processability of this platform, which exhibit lower detection limits for ALP and BChE with a detection limit for BChE an order of magnitude lower than those of the other reported paper-based detection methods. The practicability and efficiency of this platform are further demonstrated through the analysis of clinical serum samples. This innovative platform exhibits great potential as a facile yet robust approach for simultaneous, accurate, and on-site visual detection of multiple enzyme activities in authentic samples.

Application of Cyclodextrin for Cancer Immunotherapy.

Tumor immunotherapy, compared with other treatment strategies, has the notable advantage of a long-term therapeutic effect for preventing metastasis and the recurrence of tumors, thus holding great potential for the future of advanced tumor therapy. However, due to the poor water solubility of immune modulators and immune escape properties of tumor cells, the treatment efficiency of immunotherapy is usually significantly reduced. Cyclodextrin (CD) has been repeatedly highlighted to be probably one of the most investigated building units for cancer therapy due to its elegant integration of an internal hydrophobic hollow cavity and an external hydrophilic outer surface. The application of CD for immunotherapy provides new opportunities for overcoming the aforementioned obstacles. However, there are few published reviews, to our knowledge, summarizing the use of CD for cancer immunotherapy. For this purpose, this paper provides a comprehensive summary on the application of CD for immunotherapy with an emphasis on the role, function, and reported strategies of CD in mediating immunotherapy. This review summarizes the research progress made in using CD for tumor immunotherapy, which will facilitate the generation of various CD-based immunotherapeutic delivery systems with superior anticancer efficacy.

Expanding Cyclic Topology-Based Biomedical Polymer Panel: Universal Synthesis of Hetero-"8"-Shaped Copolymers and Topological Modulation of Polymer Degradation.

8-Shaped copolymers with two macrocycles connected together represent an interesting cyclic topology-derived polymer species due to the simultaneous incorporation of two cyclic moieties and the reported unique physical and chemical properties. To provide a proof-of-concept for a broad readership on biomedical polymers, a well-defined hetero-8-shaped amphiphilic copolymer, cyclic-poly(oligo(ethylene glycol)monomethyl ether methacrylate)-b-cyclic PCL (cPOEGMA-b-cPCL) is synthesized by an elegant integration of intrachain click cyclization and interchain click coupling. The potential of the self-assembled micelles of cPOEGMA-b-cPCL for controlled drug release is evaluated by in vitro drug loading and drug release, cellular uptake, cytotoxicity, and degradation studies. Most importantly, the micelles based on cPOEGMA-b-cPCL show much slower degradation profiles than the previously reported linear counterpart, POEGMA-b-PCL and tadpole-shaped analog, PEG-b-cPCL because of the presence of cyclic hydrophilic POEGMA segment. Therefore, this study not only develops a robust strategy for a universal precise synthesis of well-defined hetero-8-shaped copolymers based on diverse vinyl and ring-structured monomers, but also reveals the first modulation of polymer degradation property by topological control of the nondegradable moiety in the polymer construct through advanced macromolecular engineering.

Facile Fabrication of Nanoparticles with Dual-Targeting Ligands for Precise Hepatocellular Carcinoma Therapy In Vitro and In Vivo.

Efficient hepatocellular carcinoma (HCC) therapy remains a significant challenge due to the unsatisfactory targeting efficiency of nanoparticles (NPs) with either a passive targeting or a single active targeting property. Although a dual-targeting mechanism-based strategy can promote the partial targeting efficiency, most of the reported NPs with dual-targeting properties generally suffer from sophisticated chemical design, multistep synthesis, and purification procedures, leading to batch-to-batch variation and difficulties in scalable production. To develop a facile yet efficient strategy toward dual-targeting ligand-functionalized NPs for precise HCC therapy and potential clinical translation, folic acid (FA) was readily introduced as a hydrophobic and targeting component to a hydrophilic macromolecular prodrug, galactosylated chitosan-5-fluorouracil acetic acid (GC-FU), to afford FA-GC-FU formulation that can self-assemble into NPs driven by the solubility variation of FA and GC-FU without the necessity of previously used physical cross-linking. The resulting nanoparticles of FA-GC-FU can target the overexpressed asialoglycoprotein receptors (ASGPRs) and folate receptors (FRs) on the surface of HCC cells, respectively, via the FA and lactobionic acid (LA) residues exposed on the surface of the NPs, leading to the maximized targeting efficiency of HCC and minimized nonspecific uptake by normal hepatocytes in vitro and in vivo. Therefore, this study not only developed a simple yet efficient strategy toward a facile fabrication of NPs with dual-targeting ligands but also presented a precise therapeutic platform for HCC with great potential for clinical translation.

In vitro and in vivo evaluation of pectin-based nanoparticles for hepatocellular carcinoma drug chemotherapy.

The fabrication and evaluation of a natural pectin-based drug delivery system are reported in this study. The drug delivery system displays specific active targeting ability to hepatocellular carcinoma due to the presence of excess galactose residues in the polymer structure as the natural targeting ligands. The system was prepared under very mild conditions in an aqueous medium containing Ca(2+) and CO3(2-) ions, generating uniform pectin-based nanoparticles with an average diameter of 300 nm, and the drug-loading content of anticancer drug 5-fluorouracil (5-FU) is around 24.8%. Cytotoxicity study of the 5-FU-loaded nanoparticles (5-FU-NPs) in HepG2 and A549 cell lines demonstrated their greater potency in killing cancer cells with overexpressed asialoglycoprotein receptor (ASGPR) on the cell surface, compared to that of the free drug. Pharmacokinetics study using Sprague-Dawley (SD) rats further confirmed that the drug-loaded nanoparticles showed a much longer half-life in the circulation fluids than the free drug. Tissue distribution was investigated on Kunming mice, and the results also demonstrated that the 5-FU-NPs has a long circulation effect. Taken together, the pectin-based drug delivery systems exhibit size-induced prolonged circulation as well as ASGP receptor-mediated targeting ability to cancer cell lines; therefore, it is a promising platform for the treatment of hepatocellular carcinoma.

Injectable hydrogels as emerging drug-delivery platforms for tumor therapy.

Tumor therapy continues to be a prominent field within biomedical research. The development of various drug carriers has been propelled by concerns surrounding the side effects and targeting efficacy of various chemotherapeutic drugs and other therapeutic agents. These carriers strive to enhance drug concentration at tumor sites, minimize systemic side effects, and improve therapeutic outcomes. Among the reported delivery systems, injectable hydrogels have emerged as an emerging candidate for the in vivo delivery of chemotherapeutic drugs due to their minimal invasive drug delivery properties. This review systematically summarizes the composition and preparation methodologies of injectable hydrogels and further highlights the delivery mechanisms of diverse drugs using these hydrogels for tumor therapy, along with an in-depth discussion on the optimized therapeutic efficiency of drugs encapsulated within the hydrogels. The work concludes by providing a dynamic forward-looking perspective on the potential challenges and possible solutions of the in situ injectable hydrogels for non-surgical and real-time diagnostic applications.

Liposome-based nanomedicine for immune checkpoint blocking therapy and combinatory cancer therapy.

The discovery of immune checkpoint (IC) has led to a wave of leap forward in cancer immunotherapy that represents probably the most promising strategy for cancer therapy. However, the clinical use of immune checkpoint block (ICB) therapy is limited by response rates and side effects. A strategy that addresses the limitations of ICB therapies through combination therapies, using nanocarriers as mediators, has been mentioned in numerous research papers. Liposomes have been probably one of the most extensively used nanocarriers for clinical applications, with broad drug delivery and high safety. A timely review on this hot subject of research, i.e., the application of liposomes for ICB, is thus highly desirable for both fundamental and clinical translatable studies, but remains, to our knowledge, unexplored so far. For this purpose, this review is composed to address the dilemma of ICB therapy and the reasons for this dilemma. We later describe how other cancer treatments have broken this dilemma. Finally, we focus on the role of liposomes in various combinatory cancer therapy. This review is believed to serve as a guidance for the rational design and development of liposome for immunotherapy with enhanced therapeutic efficiency.

Immunomodulatory Peptides for Tumor Treatment.

Peptides exhibit various biological activities, including biorecognition, cell targeting, and tumor penetration, and can stimulate immune cells to elicit immune responses for tumor immunotherapy. Peptide self-assemblies and peptide-functionalized nanocarriers can reduce the effect of various biological barriers and the degradation by peptidases, enhancing the efficiency of peptide delivery and improving antitumor immune responses. To date, the design and development of peptides with various functionalities have been extensively reviewed for enhanced chemotherapy; however, peptide-mediated tumor immunotherapy using peptides acting on different immune cells, to the knowledge, has not yet been summarized. Thus, this work provides a review of this emerging subject of research, focusing on immunomodulatory anticancer peptides. This review introduces the role of peptides in the immunomodulation of innate and adaptive immune cells, followed by a link between peptides in the innate and adaptive immune systems. The peptides are discussed in detail, following a classification according to their effects on different innate and adaptive immune cells, as well as immune checkpoints. Subsequently, two delivery strategies for peptides as drugs are presented: peptide self-assemblies and peptide-functionalized nanocarriers. The concluding remarks regarding the challenges and potential solutions of peptides for tumor immunotherapy are presented.

Enhancing myocardial infarction treatment through bionic hydrogel-mediated spatial combination therapy via mtDNA-STING crosstalk modulation.

Myocardial infarction (MI)-induced impaired cardiomyocyte (CM) mitochondrial function and microenvironmental inflammatory cascades severely accelerate the progression of heart failure for compromised myocardial repair. Modulation of the crosstalk between CM mitochondrial DNA (mtDNA) and STING has been recently identified as a robust strategy in enhancing MI treatment, but remains seldom explored. To develop a novel approach that can address persistent myocardial injury using this crosstalk, we report herein construction of a biomimetic hydrogel system, Rb1/PDA-hydrogel comprised of ginsenoside Rb1/polydopamine nanoparticles (Rb1/PDA NPs)-loaded carboxylated chitosan, 4-arm-PEG-phenylboronic acid (4-arm-PEG-PBA), and 4-arm-PEG-dopamine (4-arm-PEG-DA) crosslinked networks. An optimized hydrogel formulation presents not only desired adhesion properties to the surface of the myocardium, but also adaptability for deep myocardial injection, resulting in ROS scavenging, CM mitochondrial function protection, M1 macrophage polarization inhibition through the STING pathway, and angiogenesis promotion via an internal-external spatial combination. The enhanced therapeutic efficiency is supported by the histological analysis of the infarcted area, which shows that the fibrotic area of the MI rats decreases from 58.4% to 5.5%, the thickness of the left ventricular wall increases by 1-fold, and almost complete recovery of cardiac function after 28 days of treatment. Overall, this study reported the first use of a strong adhesive and injectable hydrogel with mtDNA and STING signaling characteristics for enhanced MI treatment via an internal-external spatial combination strategy.

Current advances in modulating tumor hypoxia for enhanced therapeutic efficacy.

Hypoxia is a common feature of most solid tumors, which promotes the proliferation, invasion, metastasis, and therapeutic resistance of tumors. Researchers have been developing advanced strategies and nanoplatforms to modulate tumor hypoxia to enhance therapeutic effects. A timely review of this rapidly developing research topic is therefore highly desirable. For this purpose, this review first introduces the impact of hypoxia on tumor development and therapeutic resistance in detail. Current developments in the construction of various nanoplatforms to enhance tumor treatment in response to hypoxia are also systematically summarized, including hypoxia-overcoming, hypoxia-exploiting, and hypoxia-disregarding strategies. We provide a detailed discussion of the rationale and research progress of these strategies. Through a review of current trends, it is hoped that this comprehensive overview can provide new prospects for clinical application in tumor treatment. STATEMENT OF SIGNIFICANCE: As a common feature of most solid tumors, hypoxia significantly promotes tumor progression. Advanced nanoplatforms have been developed to modulate tumor hypoxia to enhanced therapeutic effects. In this review, we first introduce the impact of hypoxia on tumor progression. Current developments in the construction of various nanoplatforms to enhance tumor treatment in response to hypoxia are systematically summarized, including hypoxia-overcoming, hypoxia-exploiting, and hypoxia-disregarding strategies. We discuss the rationale and research progress of the above strategies in detail, and finally introduce future challenges for treatment of hypoxic tumors. By reviewing the current trends, this comprehensive overview can provide new prospects for clinical translatable tumor therapy.

A multivalent polyphenol-metal-nanoplatform for cascade amplified chemo-chemodynamic therapy.

Chemodynamic therapy (CDT), as an emerging therapeutic strategy, kills cancer cells by converting intracellular hydrogen peroxide (H2O2) into cytotoxic oxidizing hydroxyl radicals (⋅OH). However, the therapeutic efficiency of CDT is compromised due to the insufficient endogenous H2O2 and metal catalysts in tumor cells. The use of multivalent polyphenols with multiple hydroxyl functions provides a facile yet robust means for efficient CDT augmentation. For this purpose, we reported herein the construction of polyphenol-metal nanoparticles (NPs) via a phenol-metal coordination strategy. The uniqueness of this study is the preparation of only one polymer construct with multivalency that can afford various supramolecular interactions for simultaneous "one-pot" loading of different therapeutic species, i.e., doxorubicin (DOX), glucose oxidases (GOD), and Fe3+ and further co-self-assembly into a stabilized nanomedicine for cascade amplified chemo-chemodynamic therapy. Specifically, the tumor intracellular acidic pH-triggered DOX release could serve for chemotherapy as well as enhance the intracellular H2O2 level. Together with the extra H2O2 and gluconic acid produced by the GOD-triggered glucose consumption, DOX@POAD-Fe@GOD NPs promoted Fe3+participation in the Fe-mediated Fenton reaction for cascade amplified chemo-chemodynamic therapy. Notably, this formulation displayed a greater anti-tumor effect with a tumor inhibition ratio 1.6-fold higher than that of free DOX in a BALB/c mice model bearing 4T1 tumors. Overall, the multivalent polyphenol-metal nanoplatform developed herein integrates chemotherapy, starvation therapy, and CDT for synergistic enhanced anticancer efficiency, which shows great potential for clinical translations. STATEMENT OF SIGNIFICANCE: Chemodynamic therapy (CDT) generally suffers from compromised therapeutic efficiency due to insufficient endogenous H2O2 and metal catalysts in tumor cells. To develop a facile yet robust strategy for efficient CDT augmentation, we reported herein construction of a multivalent polyphenol-metal nanoplatform, DOX@POAD-Fe@GOD nanoparticles (NPs) via a phenol-metal coordination strategy. This nanoplatform integrates multiple supramolecular dynamic interactions not only for simultaneously safe encapsulation of doxorubicin (DOX), Fe3+, and glucose oxidases (GOD), but also for cascade amplified chemo-chemodynamic therapy. Specifically, the intracellular acidic pH-triggered dissociation of DOX@POAD-Fe@GOD NPs promoted the release of Fe3+, DOX, and GOD for significantly increased ROS levels that can accelerate Fenton reactions for cascaded chemotherapy, starvation therapy, and CDT with amplified antitumor efficiency in vivo.

Spherical nucleic acids: emerging amplifiers for therapeutic nanoplatforms.

Gene therapy is a revolutionary treatment approach in the 21st century, offering significant potential for disease prevention and treatment. However, the efficacy of gene delivery is often compromised by the inherent challenges of gene properties and vector-related defects. It is crucial to explore ways to enhance the curative effect of gene drugs and achieve safer, more widespread, and more efficient utilization, which represents a significant challenge in amplification gene therapy advancements. Spherical nucleic acids (SNAs), with their unique physicochemical properties, are considered an innovative solution for scalable gene therapy. This review aims to comprehensively explore the amplifying contributions of SNAs in gene therapy and emphasize the contribution of SNAs to the amplification effect of gene therapy from the aspects of structure, application, and recent clinical translation - an aspect that has been rarely reported or explored thus far. We begin by elucidating the fundamental characteristics and scaling-up properties of SNAs that distinguish them from traditional linear nucleic acids, followed by an analysis of combined therapy treatment strategies, theranostics, and clinical translation amplified by SNAs. We conclude by discussing the challenges of SNAs and provide a prospect on the amplification characteristics. This review seeks to update the current understanding of the use of SNAs in gene therapy amplification and promote further research into their clinical translation and amplification of gene therapy.

Stabilized, ROS-sensitive ß-cyclodextrin-grafted hyaluronic supramolecular nanocontainers for CD44-targeted anticancer drug delivery.

Hyaluronic acid (HA)-based tumor microenvironment-responsive nanocontainers are attractive candidates for anticancer drug delivery due to HA's excellent biocompatibility, biodegradability, and CD44-targeting properties. Nevertheless, the consecutive synthesis of stabilized, stealthy, responsive HA-based multicomponent nanomedicines generally requires multi-step preparation and purification procedures, leading to batch-to-batch variation and scale-up difficulties. To develop a facile yet robust strategy for promoted translations, a silica monomer containing a cross-linkable diethoxysilyl unit was prepared to enable in situ crosslinking without any additives. Further combined with the host-guest inclusion complexation between ß-cyclodextrin-grafted HA (HA-CD) and ferrocene-functionalized polymers, ferrocene-terminated poly(oligo(ethylene glycol) methyl ether methacrylate (Fc-POEGMA) and Fc-terminated poly(ε-caprolactone)-b-poly(3-(diethoxymethylsilyl)propyl(2-(methacryloyloxy)ethyl) carbamate) (Fc-PCL-b-PDESPMA), a reactive oxygen species (ROS)-sensitive supramolecular polymer construct, Fc-POEGMA/Fc-PCL-b-PDESPMA@HA-CD was readily fabricated to integrate stealthy POEGMA, tumor active targeting HA, and an in situ cross-linkable PDESPMA sequence. Supramolecular amphiphilic copolymers with two different POEGMA contents of 25 wt% (P1) and 20 wt% (P2) were prepared via a simple physical mixing process, affording two core-crosslinked (CCL) micelles via an in situ sol-gel process of ethoxysilyl groups. The P1-based CCL micelles show not only desired colloidal stability against high dilution, but also an intracellular ROS-mimicking environment-induced particulate aggregation that is beneficial for promoted intracellular release of the loaded cargoes. Most importantly, P1-based nanomedicines exhibited greater cytotoxicity in CD44 receptor-positive HeLa cells than that in CD44 receptor-negative MCF-7 cells. Overall, this work developed HA-based nanomedicines with sufficient extracellular colloidal stability and efficient intracellular destabilization properties for enhanced anticancer drug delivery via smart integration of in situ crosslinking and supramolecular complexation.

A fully biodegradable spherical nucleic acid nanoplatform for self-codelivery of doxorubicin and miR122 for innate and adaptive immunity activation.

Facile construction of a fully biodegradable spherical nucleic acid (SNA) nanoplatform is highly desirable for clinical translations but remains rarely explored. We developed herein the first polycarbonate-based biodegradable SNA nanoplatform for self-codelivery of a chemotherapeutic drug, doxorubicin (DOX), and a human liver-specific miR122 for synergistic chemo-gene therapy of hepatocellular carcinoma (HCC). Ring-opening polymerization (ROP) of a carbonate monomer leads to a well-defined polycarbonate backbone for subsequent DOX conjugation to the pendant side chains via acidic pH-cleavage Schiff base links and miR122 incorporation to the chain termini via click coupling, affording an amphiphilic polycarbonate-DOX-miR122 conjugate, PBis-Mpa30-DOX-miR122 that can self-assemble into stabilized SNA. Besides the desired biodegradability, another notable merit of this nanoplatform is the use of miR122 not only for gene therapy but also for enhanced innate immune response. Together with the ICD-triggering effect of DOX, PBis-Mpa30-DOX-miR122 SNA-mediated DOX and miR122 codelivery leads to synergistic immunogenicity enhancement, resulting in tumor growth inhibition value (TGI) of 98.1 % significantly higher than those of the groups treated with only drug or gene in a Hepa1-6-tumor-bearing mice model. Overall, this study develops a useful strategy toward biodegradable SNA construction, and presents a drug and gene-based self-codelivery SNA with synergistic immunogenicity enhancement for efficient HCC therapy. STATEMENT OF SIGNIFICANCE: Facile construction of a fully biodegradable SNA nanoplatform is useful for in vivo applications but remains relatively unexplored likely due to the synthetic challenge. We report herein construction of a polycarbonate-based SNA nanoplatform for co-delivering a chemotherapeutic drug, DOX, and a human liver-specific miR-122 for synergistic HCC treatment. In addition to the desired biodegradability properties, this SNA nanoplatform integrates DOX-triggered ICD and miR-122-enhanced innate immunity for simultaneously activating adaptive and innate immunities, which leads to potent antitumor efficiency with a TGI value of 98.1 % in a Hepa1-6-tumor-bearing mice model.

An "All-In-One" Immunomodulator-Engineered Clinical Translatable Immunotherapy of Advanced Hepatocellular Carcinoma.

Clinical treatment of advanced hepatocellular carcinoma (HCC) remains a significant challenge. Utilizing 1-bromoacetyl-3,3-dinitroazetidine (RRx-001) to downregulate the expression of innate immune checkpoint molecule, cluster of differentiation 47 (CD47), provides a powerful means for treating advanced HCC containing abundant immunosuppressive macrophages. Herein engineering of a previously optimized Doxorubicin (DOX)-delivery nanoplatform based on sodium alginate is reported to further co-deliver RRx-001 (biotinylated aldehyde alginate-doxorubicin micelle prodrug nanoplatform, BEA-D@R) for efficient immunotherapy of advanced HCC. This groundbreaking  technique reveals the "all-in-one" immunotherapeutic functionalities of RRx-001. Besides the previously demonstrated functions of downregulating CD47 expression and increasing reactive nitrogen species (RNS) generation, another key function of RRx-001 for downregulating the expression of the adaptive immune checkpoint molecule programmed cell death 1 ligand 1 (PDL1) is first uncovered here. Combined with the reactive oxygen species (ROS) generation and an upregulated "eat me" signal level of DOX, BEA-D@R collectively increases RNS generation, enhances T-cell infiltration, and maximizes macrophage phagocytosis, leading to an average of 40% tumor elimination in a mice model bearing an initial tumor volume of ≈300 mm3 that mimics advanced HCC. Overall, the "all-in-one" immunotherapeutic functionalities of a clinical translatable nanoplatform are uncovered for enhanced immunotherapy of advanced HCC.

Engineered cyclodextrin-based supramolecular hydrogels for biomedical applications.

Cyclodextrin (CD)-based supramolecular hydrogels are polymer network systems with the ability to rapidly form reversible three-dimensional porous structures through multiple cross-linking methods, offering potential applications in drug delivery. Although CD-based supramolecular hydrogels have been increasingly used in a wide range of applications in recent years, a comprehensive description of their structure, mechanical property modulation, drug loading, delivery, and applications in biomedical fields from a cross-linking perspective is lacking. To provide a comprehensive overview of CD-based supramolecular hydrogels, this review systematically describes their design, regulation of mechanical properties, modes of drug loading and release, and their roles in various biomedical fields, particularly oncology, wound dressing, bone repair, and myocardial tissue engineering. Additionally, this review provides a rational discussion on the current challenges and prospects of CD-based supramolecular hydrogels, which can provide ideas for the rapid development of CD-based hydrogels and foster their translation from the laboratory to clinical medicine.

Spherical nucleic acids-based nanoplatforms for tumor precision medicine and immunotherapy.

Precise diagnosis and treatment of tumors currently still face considerable challenges due to the development of highly degreed heterogeneity in the dynamic evolution of tumors. With the rapid development of genomics, personalized diagnosis and treatment using specific genes may be a robust strategy to break through the bottleneck of traditional tumor treatment. Nevertheless, efficient in vivo gene delivery has been frequently hampered by the inherent defects of vectors and various biological barriers. Encouragingly, spherical nucleic acids (SNAs) with good modularity and programmability are excellent candidates capable of addressing traditional gene transfer-associated issues, which enables SNAs a precision nanoplatform with great potential for diverse biomedical applications. In this regard, there have been detailed reviews of SNA in drug delivery, gene regulation, and dermatology treatment. Still, to the best of our knowledge, there is no published systematic review summarizing the use of SNAs in oncology precision medicine and immunotherapy, which are considered new guidelines for oncology treatment. To this end, we summarized the notable advances in SNAs-based precision therapy and immunotherapy for tumors following a classification standard of different types of precise spatiotemporal control on active species by SNAs. Specifically, we focus on the structural diversity and programmability of SNAs. Finally, the challenges and possible solutions were discussed in the concluding remarks. This review will promote the rational design and development of SNAs for tumor-precise medicine and immunotherapy.

Engineered Exosomes as Theranostic Platforms for Cancer Treatment.

Tremendous progress in nanotechnology and nanomedicine has made a significant positive effect on cancer treatment by integrating multicomponents into a single multifunctional nanosized delivery system for combinatorial therapies. Although numerous nanocarriers developed so far have achieved excellent therapeutic performance in mouse models via elegant integration of chemotherapy, photothermal therapy, photodynamic therapy, sonodynamic therapy, and immunotherapy, their synthetic origin may still cause systemic toxicity, immunogenicity, and preferential detection or elimination by the immune system. Exosomes, endogenous nanosized particles secreted by multiple biological cells, could be absorbed by recipient cells to facilitate intercellular communication and content delivery. Therefore, exosomes have emerged as novel cargo delivery tools and attracted considerable attention for cancer diagnosis and treatment due to their innate stability, biological compatibility, and biomembrane penetration capacity. Exosome-related properties and functions have been well-documented; however, there are few reviews, to our knowledge, with a focus on the combination of exosomes and nanotechnology for the development of exosome-based theranostic platforms. To make a timely review on this hot subject of research, we summarize the basic information, isolation and functionalization methodologies, diagnostic and therapeutic potential of exosomes in various cancers with an emphasis on the description of exosome-related nanomedicine for cancer theranostics. The existing appealing challenges and outlook in exosome clinical translation are finally introduced. Advanced biotechnology and nanotechnology will definitely not only promote the integration of intrinsic advantages of natural nanosized exosomes with traditional synthetic nanomaterials for modulated precise cancer treatment but also contribute to the clinical translations of exosome-based nanomedicine as theranostic nanoplatforms.

Aqueous green synthesis of organic/inorganic nanohybrids with an unprecedented synergistic mechanism for enhanced near-infrared photothermal performance.

Silver sulfide (Ag2S) nanoparticles (NPs) represent one of the most popular inorganic reagents for near-infrared (NIR) photothermal therapy (PTT). However, the extensive biomedical applications of Ag2S NPs are greatly compromised by the hydrophobicity of the NPs prepared in organic solvents, their low photothermal conversion efficiency, certain surface modification-induced damage to their intrinsic properties and short circulation time. To develop a facile yet efficient green approach to overcome these shortcomings for improved properties and performance of Ag2S NPs, we report herein the construction of Ag2S@polydopamine (PDA) nanohybrids via a "one-pot" organic-inorganic hybridization strategy, which produces uniform Ag2S@PDA nanohybrids with well-modulated sizes in the range of 100-300 nm via the self-polymerization of dopamine (DA) and subsequent synergistic assembly of PDA with Ag2S NPs in a three-phase mixed medium containing water, ethanol and trimethylbenzene (TMB). Integration of dual photothermal moieties, i.e., Ag2S and PDA at a molecular level, endows Ag2S@PDA nanohybrids with synergistically enhanced NIR photothermal properties that are much better than those of either PDA or Ag2S NPs due to calculated combination indexes (CIs) of 0.3-0.7 between Ag2S NPs and PDA based on a modified Chou-Talalay method. Therefore, this study not only developed a facile "one-pot" green approach toward producing uniform Ag2S@PDA nanohybrids with well-modulated dimensions, but also revealed an unprecedented synergistic mechanism for organic/inorganic nanohybrids that is based on dual photothermal moieties providing enhanced near-infrared photothermal performance.

Hyaluronic acid-based injectable nanocomposite hydrogels with photo-thermal antibacterial properties for infected chronic diabetic wound healing.

A hydrogel wound dressing with a single functionality fails to meet the requirements for successful clinical treatment of chronic diabetic wounds that generally possess complicated microenvironments. A multifunctional hydrogel is thus highly desirable for improved clinical treatment. For this purpose, we reported herein construction of an injectable nanocomposite hydrogel with self-healing and photo-thermal properties as an antibacterial adhesive via dynamic Michael addition reaction and electrostatic interactions among three building moieties, i.e., catechol and thiol-modified hyaluronic acid (HA-CA and HA-SH), poly(hexamethylene guanidine) (PHMG), and black phosphorus nanosheets (BPs). An optimized hydrogel formulation eliminated over 99.99 % of bacteria (E. coli and S. aureus) and exhibited a free radical scavenging capability >70 % as well as photo-thermal properties in addition to viscoelastic characteristics, degradation properties in vitro, good adhesion and self-adaptation capacity. Wound healing experiments in vivo further confirmed the better performance of the developed hydrogels than that of a commercially available dressing (Tegaderm™) in promoting the healing of infected chronic wounds by preventing wound infection, decreasing inflammation, supporting collagen deposition, facilitating angiogenesis, and improving granulation tissues formation in the wound sites. Overall, the HA-based injectable composite hydrogels developed herein represent promising multifunctional wound dressings for infected diabetic wound repair.