A biomimetic cuproptosis amplifier for targeted NIR-II fluorescence/photoacoustic imaging-guided synergistic NIR-II photothermal immunotherapy.

The therapeutic efficacy of cuproptosis combined with phototheranostics is still hindered by easy copper efflux, nonspecific accumulation and limited light penetration depth. Here, a high-performance NIR-II semiconductor polymer was first synthesized through dual-donor engineering. Then a biomimetic cuproptosis amplifier (PCD@CM) was prepared by Cu(II)-mediated coordinative self-assembly of NIR-II ultrasmall polymer dots and the chemotherapeutic drug DOX, followed by camouflaging of tumor cell membranes. After homologous targeting delivery to tumor cells, overexpressed GSH in the tumor microenvironment (TME) triggers the disassembly of the amplifier and the release of therapeutic components through the reduction of Cu(II) to Cu(I), which enable NIR-II fluorescence/photoacoustic imaging-guided NIR-II photothermal therapy (PTT) and chemotherapy. The released Cu(I) induces the aggregation of lipoylated mitochondrial proteins accompanied by the loss of iron-sulfur proteins, leading to severe proteotoxic stress and eventually cuproptosis. NIR-II PTT and GSH depletion render tumor cells more sensitive to cuproptosis. The amplified cuproptosis sensitization provokes significant immune surveillance, triggering the immunogenic cell death (ICD) to promote cytotoxic T lymphocyte infiltration together with aPD-L1-mediated immune checkpoint blockade. This work proposes a new strategy to develop cuproptosis sensitization systems enhanced by NIR-II phototheranostics with homologous targeting and anti-tumor immune response capabilities.

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.

Near-infrared-II light excitation thermosensitive liposomes for photoacoustic imaging-guided enhanced photothermal-chemo synergistic tumor therapy.

Despite the great success of photothermal therapy (PTT), it still suffers from many obstacles, such as the limited penetration depth of light, thermoresistance of tumors, and limitations of mono-therapeutic modalities. Herein, second near-infrared (NIR-II, 1064 nm) light excitation thermosensitive liposomes (DG@TLs) were fabricated for photoacoustic imaging (PAI) guided enhanced PTT-chemotherapy. DG@TLs were constructed by encapsulating NIR-II light excitation semiconducting polymers into liposomes composed of phase change materials (PCMs), along with gambogic acid (GA) with chemotherapeutic and heat shock protein inhibition effects. Under 1064 nm laser irradiation, DG@TLs exhibited superior NIR-II PAI and PTT performances with deep tissue penetration while triggering the thermoresponsive release of GA based on the phase transition of PCMs from solid to liquid. The released GA could enhance the NIR-II PTT efficacy by inhibiting the activity of HSP90, reducing the thermoresistance of tumors, exhibiting significant chemotherapeutic effects, and achieving synergistic anti-tumor efficiency. This work provides a new strategy for achieving on-demand drug release and effective theranostics in deep-seated tumor regions.

NIR-II fluorescence imaging guided tumor-specific NIR-II photothermal therapy enhanced by starvation mediated thermal sensitization strategy.

Photothermal therapy (PTT) is hampered by limited light penetration depth and cell thermoresistance induced by over-expressed heat shock proteins (HSPs). Herein, we proposed a tumor-specific enhanced NIR-II PTT through the starvation mediated thermal sensitization strategy. A semiconducting polymer with superior NIR-II fluorescence imaging (FI) performance and NIR-II PTT efficacy was synthesized and encapsulated into folate modified liposomes, together with a glycolysis inhibitor, 2-deoxy-d-glucose (2DG). Upon specifically targeting folate receptors and guidance of NIR-II FI, spatiotemporal 2DG release could be achieved by the trigger of NIR-II photothermal effect. The released 2DG could not only deplete the energy supply of tumor cells by inhibiting tumor anaerobic glycolysis, but also decrease the ATP levels and hamper the production of HSPs, ultimately enhancing the tumor thermal sensitivity toward PTT. Owing to the sensitization effect of 2DG, tumor cells with overexpressed folate receptors could be significantly damaged by NIR-II PTT with an enhanced therapeutic efficiency. The work provided a promising strategy for specific starvation/NIR-II PTT synergistic therapy towards tumors.

Injectable and Thermosensitive Liposomal Hydrogels for NIR-II Light-Triggered Photothermal-Chemo Therapy of Pancreatic Cancer.

An injectable hydrogel sustained drug release system could be a promising technique for in situ treatment. Herein, an injectable hydrogel was prepared for photothermal-chemo therapy of cancer based on the thermosensitive liposomal hydrogel (Lip-Gel). The Lip-Gel system was fabricated by encapsulation of the NIR-II photothermal agent (DPP-BTz) and chemotherapy drugs (GEM) in thermosensitive liposomes and then combined with hydrogel precursor solution. The hydrogel precursor was used as an injectable flowing solution at room temperature and transferred into a cross-linked gel structure at physiological temperature. After being injected into the tumor, DPP-BTz in the Lip-Gel system can generate heat under irradiation of 1064 nm laser, breaking the thermosensitive liposomes and releasing GEM to kill tumor cells. From the treatment results, the Lip-Gel system showed a significant antitumor effect through chemo-/photothermal therapy combination therapy triggered by the NIR-II laser. This work provides a useful scheme for the development of drug delivery and drug treatment directions for local cancer therapy.

Tunable NIR Absorption Property of a Dithiolene Nickel Complex: A Promising NIR-II Absorption Material for Photothermal Therapy.

Exogenous photothermal agents absorbing in the second near-infrared optical window (NIR-II, 1000-1700 nm) have received much attention due to their use in noninvasive photothermal therapy. A small quantity of organic NIR-II photothermal agents have been exploited, and the development of organic NIR-II photothermal materials is an urgent need for biological applications. In this study, we designed and synthesized three dithiolene nickel(II) complexes with different ligands-bis(phenyl) dithiolene for NiBD-Ph, bis(fluorenyl) dithiolene for NiBD-Fl, and bis(carbazolyl) dithiolene for NiBD-Cz-and investigated their photophysical properties. These complexes exhibited ligand-dependent NIR absorption performance, centered at 854 nm for NiBD-Ph, 942 nm for NiBD-Fl, and 1010 nm for NiBD-Cz, respectively. NiBD-Cz is wrapped in ethylene oxide/propylene oxide block copolymer (F-127) through a hydrophilic-hydrophobic interaction to form water-soluble NiBD-Cz/F-127 nanoparticles (NiBD-Cz NPs), and the absorption peak of NiBD-Cz NPs are red-shifted to 1036 nm. NiBD-Cz NPs exhibit good dispersibility in water, robust photostability, and a high photothermal conversion efficiency (PCE) of 63.6% under 1064 nm laser irradiation, which is the highest PCE among metal bis(dithiolene) complexes up to now. The high PCE makes it possible to achieve better photothermal treatment effects even at low concentrations and under low-power laser irradiation.

Multifunctional Theranostic Liposomes Loaded with a Hypoxia-Activated Prodrug for Cascade-Activated Tumor Selective Combination Therapy.

Photodynamic therapy (PDT) is becoming a promising therapeutic regimen but is limited by the hypoxic microenvironment in solid tumors and the undesirable post-treatment phototoxicity side effects on normal tissues. To overcome these restrictions and enhance the antitumor therapeutic effect, near-infrared (NIR) light-activated, cancer cell-specific, hypoxia prodrug-loaded chlorin e6 liposomes were developed for tumor selective combination therapy guided by multimodal imaging. The photothermal agent indocyanine green (ICG) and hypoxia-activated prodrug tirapazamine (TPZ) were coencapsulated into the liposomes, followed by modification with cRGD and conjugation with GdIII to form ICG/TPZ@Ce6-GdIII theranostic liposomes (ITC-GdIII TLs). In the ITC-GdIII TLs, both the fluorescence and photodynamic effect of Ce6 were quenched by ICG via fluorescence resonance energy transfer. The ITC-GdIII TLs can effectively reach the tumor site through the enhanced permeability and retention effect as well as the cRGD-mediated active targeting ability. The fluorescence and photodynamic effect of Ce6 can be activated by the photothermal effect of ICG under NIR light. Upon subsequent irradiation with a 660 nm laser, the released Ce6 could kill cancer cells by generating cytotoxic singlet oxygen. Furthermore, the PDT process would induce hypoxia, which in turn activated the antitumor activity of the codelivered hypoxia-activated prodrug TPZ for a combination antitumor effect. The TLs could be utilized for multimodal imaging (fluorescence/photoacoustic/magnetic resonance imaging)-guided cascade-activated tumor inhibition with optimized therapeutic efficiency and minimized side effects, holding great potential for constructing intelligent nanotheranostics.

Multifunctional Thermosensitive Liposomes Based on Natural Phase-Change Material: Near-Infrared Light-Triggered Drug Release and Multimodal Imaging-Guided Cancer Combination Therapy.

Multifunctional theranostic nanoplatforms (NPs) in response to environment stimulations for on-demand drug release are highly desirable. Herein, the near-infrared (NIR)-absorbing dye, indocyanine green (ICG), and the antitumor drug, doxorubicin (DOX), were efficiently coencapsulated into the thermosensitive liposomes based on natural phase-change material. Folate and conjugated gadolinium (Gd) chelate-modified liposome shells enhance active targeting and magnetic resonance performance of the NPs while maintaining the size of the NPs. The ICG/DOX-loaded and gadolinium chelate conjugated temperature-sensitive liposome nanoplatforms (ID@TSL-Gd NPs) exhibited NIR-triggered drug release and prominent chemo-, photothermal, and photodynamic therapy properties. With the coencapsulated ICG, DOX, and the conjugated gadolinium chelates, the ID@TSL-Gd NPs can be used for triple-modal imaging (fluorescence/photoacoustic/magnetic resonance imaging)-guided combination tumor therapy (chemotherapy, photothermotherapy, and photodynamic therapy). After tail vein injection, the ID@TSL-Gd NPs accumulated effectively in subcutaneous HeLa tumor of mice. The tumor was effectively suppressed by accurate imaging-guided NIR-triggered phototherapy and chemotherapy, and no tumor regression and side effects were observed. In summary, the prepared ID@TSL-Gd NPs achieved multimodal imaging-guided cancer combination therapy, providing a promising platform for improving diagnosis and treatment of cancer.

Enhanced photoelectrochemical aptasensing platform based on exciton energy transfer between CdSeTe alloyed quantum dots and SiO2@Au nanocomposites.

High-efficient exciton energy transfer between CdSeTe alloyed quantum dots and SiO2@Au nanocomposites was applied to develop an enhanced photoelectrochemical aptasensing platform with ultrahigh sensitivity, good selectivity, reproducibility and stability.