Helper Lipid-Enhanced mRNA Delivery for Treating Metabolic Dysfunction-Associated Fatty Liver Disease.

Lipid nanoparticles (LNPs) represent the forefront of mRNA delivery platforms, yet achieving precise delivery to specific cells remains a challenge. The current targeting strategies complicate the formulation and impede the regulatory approval process. Here, through a straightforward regulation of helper lipids within LNPs, we introduce an engineered LNP designed for targeted delivery of mRNA into hepatocytes for metabolic dysfunction-associated fatty liver disease (MAFLD) treatment. The optimized LNP, supplied with POPC as the helper lipid, exhibits a 2.49-fold increase in mRNA transfection efficiency in hepatocytes compared to that of FDA-approved LNPs. CTP:phosphocholine cytidylyltransferase α mRNA is selected for delivery to hepatocytes through the optimized LNP system for self-calibration of phosphatidylcholine levels to prevent lipid droplet expansion in MAFLD. This strategy effectively regulates lipid homeostasis, while demonstrating proven biosafety. Our results present a mRNA therapy for MAFLD and open a new avenue for discovering potent lipids enabling mRNA delivery to specific cells.

Enzyme-Activatable Interferon-Poly(α-amino acid) Conjugates for Tumor Microenvironment Potentiation.

Protein-polymer conjugation is a clinically validated approach to enhanced pharmacokinetic properties. However, the permanent attachment of polymers often leads to irreversibly reduced protein bioactivity and poor tissue penetration. As such, the use of protein-polymer conjugates for solid tumors remains elusive. Herein, we report a simple strategy using enzyme-activatable and size-shrinkable protein-polypeptide conjugates to overcome this clinical challenge. Briefly, a matrix metalloproteinase (MMP)-responsive peptide sequence is introduced between a therapeutic protein interferon (IFN) and a synthetic polypeptide P(EG3Glu)20. The resulting site-specific MMP-responsive conjugate, denoted as PEP20-M-IFN, can, therefore, release the attached P(EG3Glu)20 to achieve both protein activation and deep penetration into the tumor microenvironment (TME). Compared to a similarly produced nonresponsive analogue conjugate PEP20-IFN, our results find PEP20-M-IFN to show higher bioactivity in vitro, improved tumor retention, and deeper penetration in a MMP2-dependent manner. Moreover, systemic administration of PEP20-M-IFN shows outstanding antitumor efficacy in both OVCAR3 and SKOV3 ovarian tumor models in mice. This work highlights the releasable PEPylation strategy for protein drug potentiation at the TME and opens up new opportunities in clinics for the treatment of malignant solid tumors.

Fluorescent metallacycle-cored polymers via covalent linkage and their use as contrast agents for cell imaging.

The covalent linkage of supramolecular monomers provides a powerful strategy for constructing dynamic polymeric materials whose properties can be readily tuned either by the selection of monomers or the choice of functional linkers. In this strategy, the stabilities of the supramolecular monomers and the reactions used to link the monomers are crucial because such monomers are normally dynamic and can disassemble during the linking process, leading to mixture of products. Therefore, although noncovalent interactions have been widely introduced into metallacycle structures to prepare metallosupramolecular polymers, metallacycle-cored polymers linked by covalent bonds have been rarely reported. Herein, we used the mild, highly efficient amidation reaction between alkylamine and N-hydroxysuccinimide-activated carboxylic acid to link the pendent amino functional groups of a rhomboidal metallacycle 10 to give metallacycle-cored polymers P1 and P2, which further yielded nanoparticles at low concentration and transformed into network structures as the concentration increased. Moreover, these polymers exhibited enhanced emission and showed better quantum yields than metallacycle 10 in methanol and methanol/water (1/9, vol/vol) due to the aggregation-induced emission properties of a tetraphenylethene-based pyridyl donor, which serves as a precursor for metallacycle 10. The fluorescence properties of these polymers were further used in cell imaging, and they showed a significant enrichment in lung cells after i.v. injection. Considering the anticancer activity of rhomboidal Pt(II) metallacycles, this type of fluorescent metallacycle-cored polymers can have potential applications toward lung cancer treatment.

Spatial Targeting of Tumor-Associated Macrophages and Tumor Cells with a pH-Sensitive Cluster Nanocarrier for Cancer Chemoimmunotherapy.

Chemoimmunotherapy, which combines chemotherapeutics with immune-modulating agents, represents an appealing approach for improving cancer therapy. To optimize its therapeutic efficacy, differentially delivering multiple therapeutic drugs to target cells is desirable. Here we developed an immunostimulatory nanocarrier (denoted as BLZ-945SCNs/Pt) that could spatially target tumor-associated macrophages (TAMs) and tumor cells for cancer chemoimmunotherapy. BLZ-945SCNs/Pt undergo supersensitive structure collapse in the prevascular regions of tumor tissues and enable the simultaneous release of platinum (Pt)-prodrug conjugated small particles and BLZ-945, a small molecule inhibitor of colony stimulating factor 1 receptor (CSF-1R) of TAMs. The released BLZ-945 can be preferentially taken up by TAMs to cause TAMs depletion from tumor tissues, while the small particles carrying Pt-prodrug enable deep tumor penetration as well as intracellularly specific drug release to kill more cancer cells. Our studies demonstrate that BLZ-945SCNs/Pt outperform their monotherapy counterparts in multiple tumor models. The underlying mechanism studies suggest that the designer pH-sensitive codelivery nanocarrier not only induces apoptosis of tumor cells but also modulates the tumor immune environment to eventually augment the antitumor effect of CD8+ cytotoxic T cells through TAMs depletion.

Revealing the Cytotoxicity of Residues of Phosphazene Catalysts Used for the Synthesis of Poly(ethylene oxide).

We herein report a case study on the toxicity of residual catalyst in metal-free polymer. Eight-arm star-like poly(ethylene oxide)s were successfully synthesized via phosphazene-catalyzed ring-opening polymerization of ethylene oxide using sucrose as an octahydroxy initiator. The products were subjected to MTT assay using human cancer cell lines (MDA-MB-231 and A2780). Comparison between the crude and purified products clearly revealed that the residual phosphazenium salts were considerably cytotoxic, regardless of the anionic species, and that the cytotoxicity of more bulky t-BuP4 salt was higher than that of t-BuP2 salt. Such results have therefore put forward the necessity for removal of the catalyst residues from PEO-based polymers synthesized through phosphazene catalysis for biorelated applications and for the development of less or nontoxic organocatalysts for such polymers.

Radioluminescent gold nanocages with controlled radioactivity for real-time in vivo imaging.

Cerenkov luminescence imaging based on light emission from the decay of radionuclides has recently drawn great interest in molecular imaging. In this paper, we report for the first time the Cerenkov luminescence phenomenon of (198)Au isotope, as well as a facile route to the preparation of radioluminescent Au nanocages without additional radiolabeling or dye conjugation. The specific radioactivity of the Au nanocages could be easily and precisely controlled by varying the concentration of H(198)AuCl(4) precursor used for the galvanic replacement reaction. The direct incorporation of (198)Au atoms into the structure of Au nanocages enabled the ability of accurate analysis and real-time imaging in vivo. Furthermore, under biological conditions the radioactive Au nanocages were shown to emit light with wavelengths in the visible and near-infrared regions, enabling luminescence imaging of the whole mice in vivo, as well as the organs ex vivo. When combined with their favorable scattering and absorption properties in the near-infrared region, the radioactive Au nanocages can serve as a new platform for multimodality imaging and will have a significant impact on both small animal and clinical imaging.

Robust synthesis of gold cubic nanoframes through a combination of galvanic replacement, gold deposition, and silver dealloying.

A facile, robust approach to the synthesis of Au cubic nanoframes is described. The synthesis involves three major steps: 1) preparation of Au-Ag alloyed nanocages using a galvanic replacement reaction between Ag nanocubes and HAuCl4 ; 2) deposition of thin layers of pure Au onto the surfaces of the nanocages by reducing HAuCl4 with ascorbic acid, and; 3) formation of Au cubic nanoframes through a dealloying process with HAuCl4 . The key to the formation of Au cubic nanoframes is to coat the surfaces of the Au-Ag nanocages with sufficiently thick layers of Au before they are dealloyed. The Au layer could prevent the skeleton of a nanocage from being fragmented during the dealloying step. The as-prepared Au cubic nanoframes exhibit tunable localized surface plasmon resonance peaks in the near-infrared region, but with much lower Ag content as compared with the initial Au-Ag nanocages.

Lipase-sensitive polymeric triple-layered nanogel for "on-demand" drug delivery.

We report a new strategy for differential delivery of antimicrobials to bacterial infection sites with a lipase-sensitive polymeric triple-layered nanogel (TLN) as the drug carrier. The TLN was synthesized by a convenient arm-first procedure using an amphiphilic diblock copolymer, namely, monomethoxy poly(ethylene glycol)-b-poly(ε-caprolactone), to initiate the ring-opening polymerization of the difunctional monomer 3-oxapentane-1,5-diyl bis(ethylene phosphate). The hydrophobic poly(ε-caprolactone) (PCL) segments collapsed and surrounded the polyphosphoester core, forming a hydrophobic and compact molecular fence in aqueous solution which prevented antibiotic release from the polyphosphoester core prior to reaching bacterial infection sites. However, once the TLN sensed the lipase-secreting bacteria, the PCL fence of the TLN degraded to release the antibiotic. Using Staphylococcus aureus (S. aureus) as the model bacterium and vancomycin as the model antimicrobial, we demonstrated that the TLN released almost all the encapsulated vancomycin within 24 h only in the presence of S. aureus, significantly inhibiting S. aureus growth. The TLN further delivered the drug into bacteria-infected cells and efficiently released the drug to kill intracellular bacteria. This technique can be generalized to selectively deliver a variety of antibiotics for the treatment of various infections caused by lipase-secreting bacteria and thus provides a new, safe, effective, and universal approach for the treatment of extracellular and intracellular bacterial infections.

Nitric Oxide Induces Immunogenic Cell Death and Potentiates Cancer Immunotherapy.

Tumor cells undergoing immunogenic cell death (ICD) release immunogenic damage-associated molecular patterns (DAMPs) to trigger a long-term protective antitumor response. ICD can be induced by certain pathogens, chemotherapeutics, and physical modalities. In this work, we demonstrate that a gaseous molecule, specifically nitric oxide (NO), can induce a potent ICD effect. NO exerts cytotoxic effects that are accompanied by the emission of DAMPs based on the endoplasmic reticulum stress and mitochondrial dysfunction pathways. Released DAMPs elicit immunological protection against a subsequent rechallenge of syngeneic tumor cells in immunocompetent mice. We prepare polynitrosated polyesters with high NO storage capacity through a facile polycondensation reaction followed by a postsynthetic modification. The polynitrosated polyesters-based NO nanogenerator (NanoNO) that enables efficient NO delivery and controlled NO release in tumors induces a sufficient ICD effect. In different immune-intact models of tumors, the NanoNO exhibits significant tumor growth suppression and increases the local dose of immunogenic signals and T cell infiltrations, ultimately prolonging survival. In addition, the NanoNO synergizes with the PD-1 blockade to prevent metastasis. We conclude not only that NO is a potent ICD inducer for cancer immunotherapy but also that it expands the range of ICD inducers into the field of gaseous molecules.

Redox-responsive nanoparticles from the single disulfide bond-bridged block copolymer as drug carriers for overcoming multidrug resistance in cancer cells.

Multidrug resistance (MDR) is a major impediment to the success of cancer chemotherapy. The intracellular accumulation of drug and the intracellular release of drug molecules from the carrier could be the most important barriers for nanoscale carriers in overcoming MDR. We demonstrated that the redox-responsive micellar nanodrug carrier assembled from the single disulfide bond-bridged block polymer of poly(ε-caprolactone) and poly(ethyl ethylene phosphate) (PCL-SS-PEEP) achieved more drug accumulation and retention in MDR cancer cells. Such drug carrier rapidly released the incorporated doxorubicin (DOX) in response to the intracellular reductive environment. It therefore significantly enhanced the cytotoxicity of DOX to MDR cancer cells. It was demonstrated that nanoparticular drug carrier with either poly(ethylene glycol) or poly(ethyl ethylene phosphate) (PEEP) shell increased the influx but decreased the efflux of DOX by the multidrug resistant MCF-7/ADR breast cancer cells, in comparison with the direct incubation of MCF-7/ADR cells with DOX, which led to high cellular retention of DOX. Nevertheless, nanoparticles bearing PEEP shell exhibited higher affinity to the cancer cells. The shell detachment of the PCL-SS-PEEP nanoparticles caused by the reduction of intracellular glutathione significantly accelerated the drug release in MCF-7/ADR cells, demonstrated by the flow cytometric analyses, which was beneficial to the entry of DOX into the nuclei of MCF-7/ADR cells. It therefore enhanced the efficiency in overcoming MDR of cancer cells, which renders the redox-responsive nanoparticles promising in cancer therapy.

Environmentally Adaptive Shape-Morphing Microrobots for Localized Cancer Cell Treatment.

Microrobots have attracted considerable attention due to their extensive applications in microobject manipulation and targeted drug delivery. To realize more complex micro-/nanocargo manipulation (e.g., encapsulation and release) in biological applications, it is highly desirable to endow microrobots with a shape-morphing adaptation to dynamic environments. Here, environmentally adaptive shape-morphing microrobots (SMMRs) have been developed by programmatically encoding different expansion rates in a pH-responsive hydrogel. Due to a combination with magnetic propulsion, a shape-morphing microcrab (SMMC) is able to perform targeted microparticle delivery, including gripping, transporting, and releasing by "opening-closing" of a claw. As a proof-of-concept demonstration, a shape-morphing microfish (SMMF) is designed to encapsulate a drug (doxorubicin (DOX)) by closing its mouth in phosphate-buffered saline (PBS, pH ∼ 7.4) and release the drug by opening its mouth in a slightly acidic solution (pH < 7). Furthermore, localized HeLa cell treatment in an artificial vascular network is realized by "opening-closing" of the SMMF mouth. With the continuous optimization of size, motion control, and imaging technology, these magnetic SMMRs will provide ideal platforms for complex microcargo operations and on-demand drug release.

Poly(ε-caprolactone)-block-poly(ethyl ethylene phosphate) micelles for brain-targeting drug delivery: in vitro and in vivo valuation.

PURPOSE: The purpose of this work was to investigate the potential of poly(ε-caprolactone)-block-poly(ethyl ethylene phosphate) (PCL-PEEP) micelles for brain-targeting drug delivery. METHOD: The coumarin-6-loaded PCL-PEEP micelles (CMs) were prepared and characterized. The cellular uptake of CMs was evaluated on in vitro model of brain-blood barrier (BBB), and the brain biodistribution of CMs in ICR mice was investigated. RESULTS: PCL-PEEP could self-assemble into 20 nm micelles in water with the critical micelle concentration (CMC) 0.51 µg/ml and high coumarin-6 encapsulation efficiency (92.5 ± 0.7%), and the micelles were stable in 10% FBS with less than 25% leakage of incorporated coumarin-6 during 24 h incubation at 37°C. The cellular uptake of CMs by BBB model was significantly higher and more efficient than coumarin-6 solution (CS) at 50 ng/ml. Compared with CS, 2.6-fold of coumarin-6 was found in the brains of CM-treated mice, and C(max) of CMs was 4.74% of injected dose/g brain. The qualitative investigation on the brain distribution of CMs indicated that CMs were prone to accumulate in hippocampus and striatum. CONCLUSION: These results suggest that PCL-PEEP micelles could be a promising brain-targeting drug delivery system with low toxicity.

Protein Binding Affinity of Polymeric Nanoparticles as a Direct Indicator of Their Pharmacokinetics.

Polymeric nanoparticles (NPs) are an important category of drug delivery systems, and their in vivo fate is closely associated with delivery efficacy. Analysis of the protein corona on the surface of NPs to understand the in vivo fate of different NPs has been shown to be reliable but complicated and time-consuming. In this work, we establish a simple approach for predicting the in vivo fate of polymeric NPs. We prepared a series of poly(ethylene glycol)-block-poly(d,l-lactide) (PEG-b-PLA) NPs with different protein binding behaviors by adjusting their PEG densities, which were determined by analyzing the serum protein adsorption. We further determined the protein binding affinity, denoted as the equilibrium association constant (KA), to correlate with in vivo fate of NPs. The in vivo fate, including blood clearance and Kupffer cell uptake, was studied, and the maximum concentration (Cmax), the area under the plasma concentration-time curve (AUC), and the mean residence time (MRT) were negatively linearly dependent, while Kupffer cell uptake was positively linearly dependent on KA. Subsequently, we verified the reliability of the approach for in vivo fate prediction using poly(methoxyethyl ethylene phosphate)-block-poly(d,l-lactide) (PEEP-b-PLA) and poly(vinylpyrrolidone)-block-poly(d,l-lactide) (PVP-b-PLA) NPs, and the linear relationship between the KA value and their PK parameters further suggests that the protein binding affinity of polymeric NPs can be a direct indicator of their pharmacokinetics.

Shell-detachable micelles based on disulfide-linked block copolymer as potential carrier for intracellular drug delivery.

Aiming at development of a micellar nanoparticle system for intracellular drug release triggered by glutathione in tumor cells, a disulfide-linked biodegradable diblock copolymer of poly(epsilon-caprolactone) and poly(ethyl ethylene phosphate) was synthesized. It formed biocompatible micelles loaded with doxorubicin in aqueous solution but detached the shell material under glutathione stimulus, resulting in rapid drug release with destruction of micellar structure. These glutathione-sensitive micelles also rapidly released the drug molecules intracellularly and led to enhanced growth inhibition to A549 tumor cells, suggesting that this nanoparticle system may have potential for improving drug delivery efficacy.

Thermoresponsive block copolymers of poly(ethylene glycol) and polyphosphoester: thermo-induced self-assembly, biocompatibility, and hydrolytic degradation.

Novel thermoresponsive block copolymers of poly(ethylene glycol) and polyphosphoester were synthesized, and the thermo-induced self-assembly, biocompatibility, and hydrolytic degradation behavior were studied. The block copolymers with various molecular weights and compositions were synthesized through ring-opening polymerization of 2-ethoxy-2-oxo-1,3,2-dioxaphospholane (EEP) and 2-isopropoxy-2-oxo-1,3,2-dioxaphospholane (PEP) using poly(ethylene glycol) monomethyl ether (mPEG) as the initiator and stannous octoate as the catalyst. The obtained block polymers exhibited thermo-induced self-assembly behavior, demonstrated by dynamic light scattering and UV-vis measurements using 1,6-diphenyl-1,3,5-hexatriene as the probe. It was found that the critical aggregation temperature (CAT) of the block copolymers shifted to higher temperature with increased molecular weight of mPEG, while copolymerization with more hydrophobic monomer PEP led to lower transition temperature; thus, the CAT can be conveniently adjusted. The block copolymers did not induce significant hemolysis and plasma protein precipitation. In vitro MTT and live/dead staining assays indicated they are biocompatible, and the biocompatibility was further demonstrated in vivo by the absence of local acute inflammatory response in mouse muscle following intramuscular injection. Unlike most frequently studied thermoresponsive poly(N-isopropylacrylamide), polyphosphoesters were hydrolytically degradable in aqueous solution that was proven by gel permeation chromatography and NMR analyses, and the degradation products were proven to be nontoxic to HEK293 cells. Therefore, with good biocompatibility and thermoresponsiveness, these biodegradable block copolymers of mPEG and polyphosphoesters are promising as stimuli-responsive materials for biomedical applications.

Block copolymer of polyphosphoester and poly(L-lactic acid) modified surface for enhancing osteoblast adhesion, proliferation, and function.

Surface modification is often needed in tissue engineering to enhance the interaction between cells and synthetic materials and improve the cytocompatibility and cellular functions. In this study, block copolymers of poly(L-lactic acid) and poly(ethyl ethylene phosphate) (PLLA-b-PEEP) were synthesized and used to modify the PLLA surface via a spin-coating process, to understand whether surface modification with polyphosphoester-based polymer will be osteoinductive for potential bone tissue engineering applications. X-ray photoelectron spectra measurements revealed that phosphorus atomic compositions after surface modification increased from 2.09% to 4.39% with increasing PEEP length of PLLA-b-PEEP from 58 to 224 units, which also led to a more hydrophilic surface property compared with unmodified PLLA. The initial osteoblast attachment and proliferation on the modified surfaces were significantly enhanced. Moreover, cellular alkaline phosphatase activity and mineral calcium depositions were also promoted by PEEP modification. The gene expression determined by reverse transcription polymerase chain reaction further revealed that type I collagen and osteocalcin expression were upregulated in osteoblasts cultured on the modified surfaces, indicating that PEEP modification might be potentially osteoinductive and favorable for further application in bone tissue engineering.

Facile syntheses of conjugated polymers for photothermal tumour therapy.

Development of photothermal materials which are able to harness sunlight and convert it to thermal energy seems attractive. Besides carbon-based nanomaterials, conjugated polymers are emerging promising photothermal materials but their facile syntheses remain challenging. In this work, by modification of a CBT-Cys click condensation reaction and rational design of the starting materials, we facilely synthesize conjugated polymers poly-2-phenyl-benzobisthiazole (PPBBT) and its dihexyl derivative with good photothermal properties. Under the irradiation of either sunlight-mimicking Xe light or near-infrared laser, we verify that PPBBT has comparable photothermal heating-up speed to that of star material single-wall carbon nanotube. Moreover, PPBBT is used to fabricate water-soluble NPPPBBT nanoparticles which maintain excellent photothermal properties in vitro and photothermal therapy effect on the tumours exposed to laser irradiation. We envision that our synthetic method provides a facile approach to fabricate conjugated polymers for more promising applications in biomedicine or photovoltaics in the near future.

Maize productivity and soil properties in the Loess Plateau in response to ridge-furrow cultivation with polyethylene and straw mulch.

Ridge-furrow with full film mulching (RFFM) is widely used in the Loess Plateau (LP) to increase maize yield. However, continuous RFFM application may cause excessive depletion of soil organic carbon (SOC) and soil water storage (SWS). The present study tested four production systems, namely, (1) RFFM; (2) ridge-furrow with polyethylene film and straw mulching (RFFSM); (3) non-contoured seedbed with film mulching (FFM); and (4) non-contoured seedbed without mulching (CK) in 2013 and 2014 to identify an optimal technique to increase maize yield yet minimizing the negative effects. SWS under RFFSM was significantly higher by 5.4% and 13.4% compared to RFFM and CK, respectively. The changes in SOC were -0.2, -0.2, and -0.4 g·kg-1 for RFFM, FFM, and CK, respectively, and 0.3 g·kg-1 for RFFSM. Increased root residue and extra external carbon input to soil under RFFSM directly contributed to SOC recovery. RFFSM had a comparable grain yield but higher water use efficiency compared to RFFM. The combination of RFFSM is promising for improving SOC stocks, water storage, and maize productivity.

Ultralong circulating choline phosphate liposomal nanomedicines for cascaded chemo-radiotherapy.

Cancer radiation therapy (RT) is limited by endogenous DNA repair of tumor cells and microenvironmental hypoxia in tumor tissues. Herein, we demonstrated an effective cancer chemo-radiotherapy strategy based on choline phosphate liposomal nanomedicines, which inhibit the intrinsic radioresistance of RT and concomitantly harness the RT-induced hypoxia to produce additional toxicity to overcome post-RT radioresistance. To achieve this strategy, a radiotherapy sensitizer, vorinostat, and a hypoxia-activated banoxantrone dihydrochloride (AQ4N) were simultaneously delivered to a tumor using liposomes composed of an inverted polarity lipid 2-((2,3-bis(oleoyloxy)propyl)dimethylammonio)ethyl ethyl phosphate (DOCPe). The DOCPe liposomes exhibited a longer blood circulation time and enhanced tumor accumulation, compared to their zwitterionic phosphocholine counterpart. The RT was sensitized by vorinostat to kill non-tolerant normoxic tumor cells efficiently. The irradiation aggravated hypoxia-activated AQ4N to further potentiate RT treatment. This chemo-radiotherapy combination showed excellent tumor treatment efficacy and is promising for future clinical translation.

Near-Infrared II Phototherapy Induces Deep Tissue Immunogenic Cell Death and Potentiates Cancer Immunotherapy.

The deep and inner beds of solid tumors lack lymphocytic infiltration and are subjected to various immune escape mechanisms. Reversing immunosuppression deep within the tumor is vital in clinical cancer therapy, however it remains a huge challenge. In this work, we have demonstrated the use of a second window near-infrared (NIR(II)) photothermal treatment to trigger more homogeneous and deeper immunogenic cancer cell death in solid tumors, thereby eliciting both innate and adaptive immune responses for tumor control and metastasis prevention. Specifically, photothermal transducers with similar components, structures, and photothermal conversion efficiencies, but different absorptions in red light, NIR(I), and NIR(II) biowindows, were constructed by controlling the self-assembly of gold nanoparticles on fluidic liposomes. In vitro, photothermal treatments induced immunogenic cell death (ICD) that were accompanied by the release of damage-associated molecular patterns (DAMPs) regardless of the wavelength of incident lasers. In vivo, NIR(II) light resulted in a more homogeneous release and distribution of DAMPs in the deeper parts of the tumors. With the induction of ICD, NIR(II) photothermal therapy simultaneously triggered both innate and adaptive immune responses and enabled efficient tumor control with 5/8 of the mice remaining tumor-free in the cancer vaccination assay. Additionally, the NIR(II) photothermal treatment in combination with checkpoint blockade therapy exerted long-term tumor control over both primary and distant tumors. Finally, using systemically administered two-dimensional polypyrrole nanosheets as a NIR(II) transducer, we achieved striking therapeutic effects against whole-body tumor metastasis via a synergistic photothermal-immunological response.