Kilogram scale facile synthesis and systematic characterization of a Gd-macrochelate as T1-weighted magnetic resonance imaging contrast agent.

To overcome the problems of commercial magnetic resonance imaging (MRI) contrast agents (CAs) (i.e., small molecule Gd chelates), we have proposed a new concept of Gd macrochelates based on the coordination of Gd3+ and macromolecules, e.g., poly(acrylic acid) (PAA). To further decrease the r2/r1 ratio of the reported Gd macrochelates that is an important factor for T1 imaging, in this study, a superior macromolecule hydrolyzed polymaleic anhydride (HPMA) was found to coordinate Gd3+. The synthesis conditions were optimized and the generated Gd-HPMA macrochelate was systematically characterized. The obtained Gd-HPMA29 synthesized in a 100 L of reactor has a r1 value of 16.35 mM-1 s-1 and r2/r1 ratio of 2.05 at 7.0 T, a high Gd yield of 92.7% and a high product weight (1074 g), which demonstrates the feasibility of kilogram scale facile synthesis. After optimization of excipients and sterilization at a high temperature, the obtained Gd-HPMA30 formulation has a pH value of 7.97, osmolality of 691 mOsmol/kg water, density of 1.145 g/mL, and viscosity of 2.2 cP at 20 â„ƒ or 1.8 cP at 37 â„ƒ, which meet all specifications and physicochemical criteria for clinical injections indicating the immense potential for clinical applications.

Phototheranostic Metal-Phenolic Networks with Antiexosomal PD-L1 Enhanced Ferroptosis for Synergistic Immunotherapy.

Tumor-derived exosome can suppress dendritic cells (DCs) and T cells functions. Excessive secretion of exosomal programmed death-ligand 1 (PD-L1) results in therapeutic resistance to PD-1/PD-L1 immunotherapy and clinical failure. Restored T cells by antiexosomal PD-L1 tactic can intensify ferroptosis of tumor cells and vice versa. Diminishing exosomal suppression and establishing a nexus of antiexosomal PD-L1 and ferroptosis may rescue the discouraging antitumor immunity. Here, we engineered phototheranostic metal-phenolic networks (PFG MPNs) by an assembly of semiconductor polymers encapsulating ferroptosis inducer (Fe3+) and exosome inhibitor (GW4869). The PFG MPNs elicited superior near-infrared II fluorescence/photoacoustic imaging tracking performance for a precise photothermal therapy (PTT). PTT-augmented immunogenic cell death relieved exosomal silencing on DC maturation. GW4869 mediated PD-L1 based exosomal inhibition revitalized T cells and enhanced the ferroptosis. This novel synergy of PTT with antiexosomal PD-L1 enhanced ferroptosis evoked potent antitumor immunity in B16F10 tumors and immunological memory against metastatic tumors in lymph nodes.

A Metal-Phenolic Nanosensitizer Performs Hydrogen Sulfide-Reprogrammed Oxygen Metabolism for Cancer Radiotherapy Intensification and Immunogenicity.

Radiotherapy (RT) is hampered by the limited oxygen in tumors, which could be potentiated via reprogramming the oxygen metabolism and increasing the oxygen utilization efficiency. Herein, a metal-phenolic nanosensitizer (Hf-PSP-DTC@PLX) was integrated via an acid-sensitive hydrogen sulfide (H2 S) donor (polyethylene glycol-co-polydithiocarbamates, PEG-DTC) and a hafnium-chelated polyphenolic semiconducting polymer (Hf-PSP) in an amphiphilic polymer (poloxamer F127, PLX). Hf-PSP-DTC@PLX elicited a high imaging performance for precise RT and generated H2 S to reduce the cellular oxygen consumption rate via mitochondrial respiration inhibition, which reprogrammed the oxygen metabolism for improvement of the tumor oxygenation. Then, Hf-sensitization could fully utilize the well-preserved oxygen to intensify RT efficacy and activate immunogenicity. Such a synergistic strategy for improvement of oxygenation and oxygen utilization would have great potential in optimizing oxygen-dependent therapeutics.

Donut-like MOFs of copper/nicotinic acid and composite hydrogels with superior bioactivity for rh-bFGF delivering and skin wound healing.

BACKGROUND: Skin injury and the resultant defects are common clinical problems, and usually lead to chronic skin ulcers and even life-threatening diseases. Copper, an essential trace element of human body, has been reported to promote the regeneration of skin by stimulating proliferation of endothelial cell and enhance angiogenesis. RESULTS: Herein, we have prepared a new donut-like metal-organic frameworks (MOF) of copper-nicotinic acid (CuNA) by a simple solvothermal reaction. The rough surface of CuNA is beneficial for loading/release basic fibroblast growth factor (bFGF). The CuNAs with/without bFGF are easily processed into a light-responsive composite hydrogel with GelMA, which not only show excellent mechanical properties, but also display superior biocompatibility, antibacterial ability and bioactivity. Moreover, in the in vivo full-thickness defect model of skin wound, the resultant CuNA-bFGF@GelMA hydrogels significantly accelerate the wound healing, by simultaneously inhibiting the inflammatory response, promoting the new blood vessels formation and the deposition of collagen and elastic fibers. CONCLUSIONS: Considering the superior biocompatibility, antibacterial ability and bioactivity, the CuNA and its composite light-responsive hydrogel system will be promising in the applications of skin and even other tissue regeneration.

Dual Role of Doxorubicin for Photopolymerization and Therapy.

In this study, we report dual roles for doxorubicin (DOX), which can serve as an antitumor drug as well as a cocatalyst for a photoliving radical polymerization. DOX enhances the polymerization rates of a broad range of monomers, including acrylamide, acrylate, and methacrylates, allowing for high monomer conversion and well-defined molecular weights under irradiation with a blue light-emitting diode light (λmax = 485 nm, 2.2 mW/cm2). Utilizing this property, the photopolymerization of N,N-diethylacrylamide was performed in the presence of a poly(oligo(ethylene glycol) methyl ether acrylate) macroreversible addition-fragmentation chain transfer (macroRAFT) agent to prepare polymeric nanoparticles via aqueous polymerization-induced self-assembly (PISA). By varying the monomer:macroRAFT ratio, spherical polymeric nanoparticles of various diameters could be produced. Most notably, DOX was successfully encapsulated into the hydrophobic core of nanoparticles during the PISA process. The DOX-loaded nanoparticles were effectively uptaken into tumor cells and significantly inhibited the proliferation of tumor cells, demonstrating that the DOX bioactivity was not affected by the polymerization reaction.

Ligand-Functionalized Poly(ethylene glycol) Particles for Tumor Targeting and Intracellular Uptake.

Drug carriers typically require both stealth and targeting properties to minimize nonspecific interactions with healthy cells and increase specific interaction with diseased cells. Herein, the assembly of targeted poly(ethylene glycol) (PEG) particles functionalized with cyclic peptides containing Arg-Gly-Asp (RGD) (ligand) using a mesoporous silica templating method is reported. The influence of PEG molecular weight, ligand-to-PEG molecule ratio, and particle size on cancer cell targeting to balance stealth and targeting of the engineered PEG particles is investigated. RGD-functionalized PEG particles (PEG-RGD particles) efficiently target U-87 MG cancer cells under static and flow conditions in vitro, whereas PEG and cyclic peptides containing Arg-Asp-Gly (RDG)-functionalized PEG (PEG-RDG) particles display negligible interaction with the same cells. Increasing the ligand-to-PEG molecule ratio improves cell targeting. In addition, the targeted PEG-RGD particles improve cell uptake via receptor-mediated endocytosis, which is desirable for intracellular drug delivery. The PEG-RGD particles show improved tumor targeting (14% ID g-1) when compared with the PEG (3% ID g-1) and PEG-RDG (7% ID g-1) particles in vivo, although the PEG-RGD particles show comparatively higher spleen and liver accumulation. The targeted PEG particles represent a platform for developing particles aimed at balancing nonspecific and specific interactions in biological systems.

Synchronous Chemoradiation Nanovesicles by X-Ray Triggered Cascade of Drug Release.

The approach of concurrent-to-synchronous chemoradiation has now been advanced by well-designed nanovesicles that permit X-ray irradiation-triggered instant drug release. The nanovesicles consist of Au nanoparticles tethered with irradiation labile linoleic acid hydroperoxide (LAHP) molecules and oxidation-responsive poly(propylene sulfide)-poly(ethylene glycol) (PPS-PEG) polymers, where DOX were loaded in the inner core of the vesicles (Au-LAHP-vDOX). Upon irradiation, the in situ formation of hydroxyl radicals from LAHP molecules triggers the internal oxidation of PPS from being hydrophobic to hydrophilic, leading to degradation of the vesicles and burst release of cargo drugs. In this manner, synchronous chemoradiation showed impressive anticancer efficacy both in vitro and in a subcutaneous mouse tumor model by one-dose injection and one-time irradiation.

Near-Infrared Semiconducting Polymer Brush and pH/GSH-Responsive Polyoxometalate Cluster Hybrid Platform for Enhanced Tumor-Specific Phototheranostics.

Tumor-specific phototheranostics is conducive to realizing precise cancer therapy. Herein, a novel tumor microenvironment (TME)-responsive phototheranostic paradigm based on the combination of semiconducting polymer brushes and polyoxometalate clusters (SPB@POM) is rationally designed. The acidic TME could drive the self-assembly of SPB@POM into bigger aggregates for enhanced tumor retention and accumulation, while the reducing TME could significantly enhance the NIR absorption of SPB@POM for significant improvement of photoacoustic imaging contrast and photothermal therapy efficacy. Therefore, the smart pH/glutathione (GSH)-responsive SPB@POM allows for remarkable phototheranostic enhancement under the unique TME, which has potential for precise tumor-specific phototheranostics with minimal side effects.

Patterned Poly(dopamine) Films for Enhanced Cell Adhesion.

Engineered materials that promote cell adhesion and cell growth are important in tissue engineering and regenerative medicine. In this work, we produced poly(dopamine) (PDA) films with engineered patterns for improved cell adhesion. The patterned films were synthesized via the polymerization of dopamine at the air-water interface of a floating bed of spherical particles. Subsequent dissolution of the particles yielded free-standing PDA films with tunable geometrical patterns. Our results show that these patterned PDA films significantly enhance the adhesion of both cancer cells and stem cells, thus showing promise as substrates for cell attachment for various biomedical applications.

Engineered Metal-Phenolic Capsules Show Tunable Targeted Delivery to Cancer Cells.

We engineered metal-phenolic capsules with both high targeting and low nonspecific cell binding properties. The capsules were prepared by coating phenolic-functionalized hyaluronic acid (HA) and poly(ethylene glycol) (PEG) on calcium carbonate templates, followed by cross-linking the phenolic groups with metal ions and removing the templates. The incorporation of HA significantly enhanced binding and association with a CD44 overexpressing (CD44+) cancer cell line, while the incorporation of PEG reduced nonspecific interactions with a CD44 minimal-expressing (CD44-) cell line. Moreover, high specific targeting to CD44+ cells can be balanced with low nonspecific binding to CD44- cells simply by using an optimized feed-ratio of HA and PEG to vary the content of HA and PEG incorporated into the capsules. Loading an anticancer drug (i.e., doxorubicin) into the obtained capsules resulted in significantly higher cytotoxicity to CD44+ cells but lower cytotoxicity to CD44- cells.

Efficient gene delivery and multimodal imaging by lanthanide-based upconversion nanoparticles.

Nanoparticles have been explored as nonviral gene carriers for years because of the simplicity of surface modification and lack of immune response. Lanthanide-based upconversion nanoparticles (UCNPs) are becoming attractive candidates for biomedical applications in virtue of their unique optical properties and multimodality imaging ability. Here, we report a UCNPs-based structure with polyethylenimine coating for both efficient gene transfection and trimodality imaging. Cytotoxicity tests demonstrated that the nanoparticles exhibited significantly decreased cytotoxicity compared to polyethylenimine polymer. Further, in vitro studies revealed that the gene carriers are able to transfer the enhanced green fluorescence protein (EGFP) plasmid DNA into Hela cells in higher transfection efficiency than PEI. Gene silencing was also examined by delivering bcl-2 siRNA into Hela cells, resulting in significant downregulation of target bcl-2 mRNA. More importantly, we demonstrated the feasibility of upconversion gene carriers to serve as effective contrast agents for MRI/CT/UCL trimodality imaging both in vitro and in vivo. The facile fabrication process, great biocompatibility, enhanced gene transfection efficiency, and great bioimaging ability can make it promising for application in gene therapy.

Multifunctional upconversion mesoporous silica nanostructures for dual modal imaging and in vivo drug delivery.

Incorporating the agents for magnetic resonance imaging (MRI), optical imaging, and therapy in one nanostructured matrix to construct multifunctional nanomedical platform has attracted great attention for simultaneous diagnostic and therapeutic applications. In this work, a facile methodology is developed to construct a multifunctional anticancer drug nanocarrier by combining the special advantages of upconversion nanoparticles and mesoporous silica. ß-NaYF4 :Yb(3+) , Er(3+) @ß-NaGdF4 :Yb(3+) is chosen as it can provide the dual modality of upconversion luminescence and MRI. Then mesoporous silica is directly coated onto the upconversion nanoparticles to form discrete, monodisperse, highly uniform, and core-shell structured nanospheres (labeled as UCNPs@mSiO2 ), which are subsequently functionalized with hydrophilic polymer poly(ethylene glycol) (PEG) to improve the colloidal stability and biocompatibility. The obtained multifunctional nanocomposites can be used as an anticancer drug delivery carrier and applied for imaging. The anticancer drug doxorubicin (DOX) is absorbed into UCNPs@mSiO2 -PEG nanospheres and released in a pH-sensitive pattern. In vitro cell cytotoxicity tests on cancer cells verify that the DOX-loaded UCNPs@mSiO2 -PEG has comparable cytotoxicity with free DOX at the same concentration of DOX. In addition, the T1 -weighted MRI that measures in aqueous solutions reveals that the contrast brightening increases with the concentration of Gd(3+) component. Upconversion luminescence images of UCNPs@mSiO2 -PEG uptaken by cells show green emission under 980 nm infrared laser excitation. Finally, the nanocomposites show low systematic toxicity and high in vivo antitumor therapy efficacy. These findings highlight the fascinating features of upconversion-mesoporous nanocomposites as multimodality imaging contrast agents and nanocarrier for drug molecules.

Multiwalled carbon nanotubes and NaYF4:Yb3+/Er3+ nanoparticle-doped bilayer hydrogel for concurrent NIR-triggered drug release and up-conversion luminescence tagging.

Bilayer thermosensitive P(NIPAm-co-AAm) hydrogel discs were prepared by a facile UV light initiation process from N-isopropylacrylamide (NIPAm) and acrylamide (AAm) monomers' cross-linking copolymerization. Poly(ethylene glycol) (PEG) as a pore-forming agent was added in order to form a porous structure and improve the water content in the hydrogel. Functional materials of NaYF4:Yb(3+)/Er(3+) nanoparticles and multiwalled carbon nanotubes (MWCNTs) were incorporated into different layers of the P(NIPAm-co-AAm) hydrogel for the purpose of up-conversion luminescence labeling and the NIR light antenna effect, respectively. Significantly improved drug release from composite hydrogels was achieved in response to 980 nm NIR light irradiation by using lysozyme as a macromolecular drug. The multifunctional hydrogel reported here provides a platform for simultaneous NIR luminescence labeling and NIR-driven drug release.

Electrospun upconversion composite fibers as dual drugs delivery system with individual release properties.

Novel multifunctional poly(ε-caprolactone)-gelatin encapsulating upconversion core/shell silica nanoparticles (NPs) composite fibers as dual drugs delivery system (DDDS), with indomethacin (IMC) and doxorubicin (DOX) releasing in individual release properties, have been designed and fabricated via electrospinning process. Uniform and monodisperse upconversion (UC) luminescent NaYF4:Yb(3+), Er(3+) nanocrystals (UCNCs) were encapsulated with mesoporous silica shells, resulting in the formation of core/shell structured NaYF4:Yb(3+), Er(3+)@mSiO2 (UCNCs@mSiO2) NPs, which can be performed as DOX delivery carriers. These UCNCs@mSiO2 NPs loading DOX then were dispersed into the mixture of poly(ε-caprolactone) (PCL) and gelatin-based electrospinning solution containing IMC, followed by the preparation of dual drug-loaded composite fibers (DDDS) via electrospinning method. The drugs release profiles of the DDDS were measured, and the results indicated that the IMC and DOX released from the electrospun composite fibers showed distinct properties. The IMC in the composite fibers presented a fast release manner, while DOX showed a sustained release behavior. Moreover, the UC luminescent intensity ratios of (2)H(11/2)/(4)S(3/2)-(4)I(15/2) to (4)F(9/2)-(4)I(15/2) from Er(3+) vary with the amounts of DOX in the system, and thus drug release can be tracked and monitored by the luminescence resonance energy transfer (LRET) mechanism.

Lipid bilayer-based biological nanoplatforms for sonodynamic cancer therapy.

Sonodynamic therapy (SDT) has been developed as a promising alternative therapeutic modality for cancer treatment, involving the synergetic application of sonosensitizers and low-intensity ultrasound. However, the antitumor efficacy of SDT is significantly limited due to the poor performance of conventional sonosensitizers in vivo and the constrained tumor microenvironment (TME). Recent breakthroughs in lipid bilayer-based nanovesicles (LBBNs), including multifunctional liposomes, exosomes, and isolated cellular membranes, have brought new insights into the advancement of SDT. Despite their distinct sources and preparation methods, the lipid bilayer structure in common allows them to be functionalized in many comparable ways to serve as ideal nanocarriers against challenges arising from the tumor-specific sonosensitizer delivery and the complicated TME. In this review, we provide a comprehensive summary of the recent advances in LBBN-based SDT, with particular attention on how LBBNs can be engineered to improve the delivery efficiency of sonosensitizers and overcome physical, biological, and immune barriers within the TME for enhanced sonodynamic cancer therapy. We anticipate that this review will offer valuable guidance in the construction of LBBN-based nanosonosensitizers and contribute to the development of advanced strategies for next-generation sonodynamic cancer therapy.

Self-delivery of metal-coordinated NIR-II nanoadjuvants for multimodal imaging-guided photothermal-chemodynamic amplified immunotherapy.

The effectiveness of phototheranostics induced immunotherapy is still hampered by limited light penetration depth, the complex immunosuppressive tumor microenvironment (TME) and the low efficiency of immunomodulator drug delivery. Herein, self-delivery and TME responsive NIR-II phototheranostic nanoadjuvants (NAs) were fabricated to suppress the growth and metastasis of melanoma through the integration of photothermal-chemodynamic therapy (PTT-CDT) and immune remodeling. The NAs were constructed by the self-assembly of ultrasmall NIR-II semiconducting polymer dots and the toll-like receptor agonist resiquimod (R848) utilizing manganese ions (Mn2+) as coordination nodes. Under acidic TME, the NAs responsively disintegrated and released therapeutic components, which enable NIR-II fluorescence/photoacoustic/magnetic resonance imaging-guided tumor PTT-CDT. Moreover, the synergistic treatment of PTT-CDT could induce significant tumor immunogenic cell death and evoke highly efficacious cancer immunosurveillance. The released R848 stimulated the maturation of dendritic cells, which both amplified the antitumor immune response by modulating and remodeling the TME. The NAs present a promising integration strategy of polymer dot-metal ion coordination and immune adjuvants for precise diagnosis and amplified anti-tumor immunotherapy against deep-seated tumors. STATEMENT OF SIGNIFICANCE: The efficiency of phototheranostics induced immunotherapy is still limited by insufficient light penetration depth, low immune response and the complex immunosuppressive tumor microenvironment (TME). In order to improve the efficacy of immunotherapy, self-delivery NIR-II phototheranostic nanoadjuvants (PMR NAs) were successfully fabricated via the facile coordination self-assembly of ultra-small NIR-II semiconducting polymer dots and toll-like receptor agonist resiquimod (R848) utilizing manganese ions (Mn2+) as coordination nodes. PMR NAs not only enable TME responsive cargo release and NIR-II fluorescence/photoacoustic/magnetic resonance imaging mediated precise localization of tumors, but also achieve synergistic photothermal-chemodynamic therapy, evoking an effective anti-tumor immune response by ICD effect. The responsively released R848 could further amplify the efficiency of immunotherapy by reversing and remodeling the immunosuppressive tumor microenvironment, thereby effectively inhibiting tumor growth and lung metastasis.

Self-Degradable Nanogels Reshape Immunosuppressive Tumor Microenvironment via Drug Repurposing Strategy to Reactivate Cytotoxic CD8+ T Cells.

Intratumoral CD8+ T cells are crucial for effective cancer immunotherapy, but an immunosuppressive tumor microenvironment (TME) contributes to dysfunction and insufficient infiltration. Drug repurposing has successfully led to new discoveries among existing clinical drugs for use as immune modulators to ameliorate immunosuppression in TME and reactivate T-cell-mediated antitumor immunity. However, due to suboptimal tumor bioavailability, the full potential of immunomodulatory effects of these old drugs has not been realized. The self-degradable PMI nanogels carrying two repurposed immune modulators, imiquimod (Imi) and metformin (Met), are reported for TME-responsive drug release. It remodels the TME through the following aspects: 1) promoting dendritic cells maturation, 2) repolarizing M2-like tumor-associated macrophages, and 3) downregulating PD-L1 expression. Ultimately, PMI nanogels reshaped the immunosuppressive TME and efficiently promote CD8+ T cell infiltration and activation. These results support that PMI nanogels can potentially be an effective combination drug for enhancing the antitumor immune response of anti-PD-1 antibodies.

Poly(acrylic acid)-modified Fe3O4 microspheres for magnetic-targeted and pH-triggered anticancer drug delivery.

Monodisperse poly(acrylic acid)-modified Fe(3)O(4) (PAA@Fe(3)O(4)) hybrid microspheres with dual responses (magnetic field and pH) were successfully fabricated. The PAA polymer was encapsulated into the inner cavity of Fe(3)O(4) hollow spheres by a vacuum-casting route and photo-initiated polymerization. TEM images show that the samples consist of monodisperse porous spheres with a diameter around 200 nm. The Fe(3)O(4) spheres, after modification with the PAA polymer, still possess enough space to hold guest molecules. We selected doxorubicin (DOX) as a model drug to investigate the drug loading and release behavior of as-prepared composites. The release of DOX molecules was strongly dependent on the pH value due to the unique property of PAA. The HeLa cell-uptake process of DOX-loaded PAA@Fe(3)O(4) was observed by confocal laser scanning microscopy (CLSM). After being incubated with HeLa cells under magnet magnetically guided conditions, the cytotoxtic effects of DOX-loaded PAA@Fe(3)O(4) increased. These results indicate that pH-responsive magnetic PAA@Fe(3)O(4) spheres have the potential to be used as anticancer drug carriers.

Tumor Microenvironment-Modulated Nanozymes for NIR-II-Triggered Hyperthermia-Enhanced Photo-Nanocatalytic Therapy via Disrupting ROS Homeostasis.

PURPOSE: Reactive oxygen species (ROS) are a group of signaling biomolecules that play important roles in the cell cycle. When intracellular ROS homeostasis is disrupted, it can induce cellular necrosis and apoptosis. It is desirable to effectively cascade-amplifying ROS generation and weaken antioxidant defense for disrupting ROS homeostasis in tumor microenvironment (TME), which has been recognized as a novel and ideal antitumor strategy. Multifunctional nanozymes are highly promising agents for ROS-mediated therapy. METHODS: This study constructed a novel theranostic nanoagent based on PEG@Cu2-xS@Ce6 nanozymes (PCCNs) through a facile one-step hydrothermal method. We systematically investigated the photodynamic therapy (PDT)/photothermal therapy (PTT) properties, catalytic therapy (CTT) and glutathione (GSH) depletion activities of PCCNs, antitumor efficacy induced by PCCNs in vitro and in vivo. RESULTS: PCCNs generate singlet oxygen (1O2) with laser (660 nm) irradiation and use catalytic reactions to produce hydroxyl radical (•OH). Moreover, PCCNs show the high photothermal performance under NIR II 1064-nm laser irradiation, which can enhance CTT/PDT efficiencies to increase ROS generation. The properties of O2 evolution and GSH consumption of PCCNs achieve hypoxia-relieved PDT and destroy cellular antioxidant defense system respectively. The excellent antitumor efficacy in 4T1 tumor-bearing mice of PCCNs is achieved through disrupting ROS homeostasis-involved therapy under the guidance of photothermal/photoacoustic imaging. CONCLUSION: Our study provides a proof of concept of "all-in-one" nanozymes to eliminate tumors via disrupting ROS homeostasis.

A metal-polyphenolic nanosystem with NIR-II fluorescence-guided combined photothermal therapy and radiotherapy.

Photothermal therapy (PTT) achieves substantive therapeutic progress in certain tumor types without exogenous agents but is hampered by the over-activated inflammatory response or tumor recurrence in some cases. Herein, we technically developed the metal-polyphenolic nanosystem with precise NIR-II fluorescence-imaging guidance for combining hafnium (Hf)-sensitized radiotherapy with PTT to regress tumor growth.