Functionally Masked Antibody to Uncouple Immune-Related Toxicities in Checkpoint Blockade Cancer Therapy.

Of the existing immunotherapy drugs in oncology, monoclonal antibodies targeting the immune checkpoint axis are preferred because of the durable responses observed in selected patients. However, the associated immune-related adverse events (irAEs), causing uncommon fatal events, often require specialized management and medication discontinuation. The study aim was to investigate our hypothesis that masking checkpoint antibodies with tumor microenvironment (TME)-responsive polymer chains can mitigate irAEs and selectively target tumors by limiting systemic exposure to patients. We devised a broadly applicable strategy that functionalizes immune checkpoint-blocking antibodies with a mildly acidic pH-cleavable poly(ethylene glycol) (PEG) shell to prevent inflammatory side effects in normal tissues. Conjugation of pH-sensitive PEG to anti-CD47 antibodies (αCD47) minimized antibody-cell interactions by inhibiting their binding ability and functionality at physiological pH, leading to prevention of αCD47-induced anemia in tumor-bearing mice. When conjugated to anti-CTLA-4 and anti-PD-1 antibodies, double checkpoint blockade-induced colitis was also ameliorated. Notably, removal of the protective shell in response to an acidic TME restored the checkpoint antibody activities, accompanied by effective tumor regression and long-term survival in the mouse model. Our results support a feasible strategy for antibody-based therapies to uncouple toxicity from efficacy and show the translational potential for cancer immunotherapy.

Curvature-sensing peptide inhibits tumour-derived exosomes for enhanced cancer immunotherapy.

Tumour-derived exosomes (T-EXOs) impede immune checkpoint blockade therapies, motivating pharmacological efforts to inhibit them. Inspired by how antiviral curvature-sensing peptides disrupt membrane-enveloped virus particles in the exosome size range, we devised a broadly useful strategy that repurposes an engineered antiviral peptide to disrupt membrane-enveloped T-EXOs for synergistic cancer immunotherapy. The membrane-targeting peptide inhibits T-EXOs from various cancer types and exhibits pH-enhanced membrane disruption relevant to the tumour microenvironment. The combination of T-EXO-disrupting peptide and programmed cell death protein-1 antibody-based immune checkpoint blockade therapy improves treatment outcomes in tumour-bearing mice. Peptide-mediated disruption of T-EXOs not only reduces levels of circulating exosomal programmed death-ligand 1, but also restores CD8+ T cell effector function, prevents premetastatic niche formation and reshapes the tumour microenvironment in vivo. Our findings demonstrate that peptide-induced T-EXO depletion can enhance cancer immunotherapy and support the potential of peptide engineering for exosome-targeting applications.

Self-immolative polymer-based immunogenic cell death inducer for regulation of redox homeostasis.

Doxorubicin (DOX), widely used as an anticancer drug, is considered an immunogenic cell death (ICD) inducer that enhances cancer immunotherapy. However, its extended application as an ICD inducer has been limited owing to poor antigenicity and inefficient adjuvanticity. To enhance the immunogenicity of DOX, we prepare a reactive oxygen species (ROS)-responsive self-immolative polymer (R-SIP) that can efficiently destroy redox homeostasis via self-immolation-mediated glutathione depletion in cancer cells. Owing to its amphiphilic nature, R-SIP self-assemble into nano-sized particles under aqueous conditions, and DOX is efficiently encapsulated inside the nanoparticles by a simple dialysis method. Interestingly, when treated with 4T1 cancer cells, DOX-encapsulated R-SIP (DR-SIP) induces the phosphorylation of eukaryotic translation initiation factor 2α and overexpression of ecto-calreticulin, resulting in endoplasmic reticulum-associated ICD. In addition, DR-SIP contributes to the maturation of dendritic cells by promoting the release of damage-associated molecular patterns (DAMPs) from cancer cells. When intravenously administered to tumor-bearing mice, DR-SIP remarkably inhibits tumor growth compared with DOX alone. Overall, DR-SIP may have the potential to elicit an immune response as an ICD inducer.

Topological beaming of light.

Nanophotonic light emitters are key components in numerous application areas because of their compactness and versatility. Here, we propose a topological beam emitter structure that takes advantage of submicrometer footprint size, small divergence angle, high efficiency, and adaptable beam shaping capability. The proposed structure consists of a topological junction of two guided-mode resonance gratings inducing a leaky Jackiw-Rebbi state resonance. The leaky Jackiw-Rebbi state leads to in-plane optical confinement with funnel-like energy flow and enhanced emission probability, resulting in highly efficient optical beam emission. In addition, the structure allows adaptable beam shaping for any desired positive definite profiles by means of Dirac mass distribution control, which can be directly encoded in lattice geometry parameters. Therefore, the proposed approach provides highly desirable properties for efficient micro-light emitters and detectors in various applications including display, solid-state light detection and ranging, laser machining, label-free sensors, optical interconnects, and telecommunications.

Geometric-phase intraocular lenses with multifocality.

We demonstrate a new type of multifocal and extended depth of focus (EDOF) intraocular lenses (IOLs) embedding µm-thin geometric phase (GP) lens layers. As an emerging approach for lens phase design, the GP modulated IOLs outperform conventional diffractive IOLs in multifocality while completely avoiding the clinically undesirable demand for additional surface patterns to standard monofocal IOL designs. The number of foci and light splitting ratio of the GP IOLs are adjusted by changing the number of stacked GP layers and the thickness of each layer. Bifocal and trifocal GP IOLs are fabricated by radial alignment of anisotropic orientation in UV-curable liquid crystal polymers. After characterizing the defocus image and modulation transfer function of the GP IOLs, it is expected that GP IOLs will alleviate the most common problems associated with multifocal and EDOF IOLs, blurred vision and photic phenomena caused by light scattering and posterior capsule opacification.

Inverse-cavity structure for low-threshold miniature lasers.

Creating micro and nano lasers, high threshold gain is an inherent problem that have critically restricted their great technological potentials. Here, we propose an inverse-cavity laser structure where its threshold gain in the shortest-cavity regime is order-of-magnitude lower than the conventional cavity configurations. In the proposed structure, a resonant feedback mechanism efficiently transfers external optical gain to the cavity mode at a higher rate for a shorter cavity, hence resulting in the threshold gain reducing with decreasing cavity length in stark contrast to the conventional cavity structures. We provide a fundamental theory and rigorous numerical analyses confirming the feasibility of the proposed structure. Remarkably, the threshold gain reduces down by a factor ~ 10-3 for a vertical-cavity surface-emitting laser structure and ~ 0.17 for a lattice-plasmonic nanocavity structure. Therefore, the proposed approach may produce extremely efficient miniature lasers desirable for variety of applications potentially beyond the present limitations.

PD-L1 siRNA-hyaluronic acid conjugate for dual-targeted cancer immunotherapy.

"Foreignization" of tumor cells via delivery of a non-self foreign antigen (Ag) into tumors is an appealing strategy to initiate anti-tumor immunity that can facilitate tumor rejection by pre-existing foreign-Ag-reactive T cells. However, the immune-suppressive factors in the tumor microenvironment (TME) limit the durable and potent immune response of these cells against tumor antigens, stressing the need for improved tumor-foreignization strategies. Here, we demonstrate that blockade of programmed cell death ligand 1 (PD-L1) on both tumor cells and dendritic cells (DCs) can markedly potentiate the induction of tumor-reactive T cells, thereby strengthening the anti-tumor immunity ignited by tumor-foreignization. Specifically, we developed a polymeric nanoconjugate (PEG-HA-OVA/PPLs), consisting of siPD-L1-based polyplexes, PEGylated hyaluronic acid as the CD44-targeting moiety, and ovalbumin (OVA) as a model foreign antigen. Notably, PEG-HA-OVA/PPLs were simultaneously delivered into CD44high tumor cells and CD44high DCs, leading to efficient cross-presentation of OVA and downregulation of PD-L1 in both cell types. Importantly, the nanoconjugate not only allowed OVA-specific T cells to vigorously reject the foreignized tumor cells but also reprogrammed the TME to elicit robust T-cell responses specific to the endogenous tumor Ags, eventually generating long-lasting protective immunity. Thus, our combination strategy represents an innovative approach for the induction of potent tumor immunity via a two-step consecutive immune boost against exogenous and endogenous tumor Ags.

Chemiluminescence resonance energy transfer-based immunostimulatory nanoparticles for sonoimmunotherapy.

Sonodynamic therapy (SDT) has recently emerged as a promising alternative to photodynamic therapy because of its applicability in treating deeply located tumors accessible by ultrasound (US). However, the therapeutic potential of conventional sonosensitizers is limited by the low quantum yield of reactive oxygen species (ROS) and poor immune responses eliciting canonical apoptosis of cancer cells. Herein, we report chemiluminescence resonance energy transfer (CRET)-based immunostimulatory nanoparticles (iCRET NPs) for sonoimmunotherapy, which not only amplify the ROS quantum yield of sonosensitizers but also generate carbon dioxide (CO2) bubbles to induce immunogenic cell death in the tumor microenvironment (TME). Owing to their CRET phenomena responsive to H2O2 in the TME, iCRET NPs exhibit strong cytotoxicity to cancer cells by producing a large quantity of ROS. Additionally, iCRET NPs effectively induce CO2-mediated immunogenic cell death by rupturing the cancer cell membrane in the presence of US, leading to the release of bare damage-associated molecular patterns, such as HSP 70 and HMGB1. Consequently, when iCRET NPs are combined with anti-PD-1 antibodies, iCRET NPs exhibit synergistic effects in 4T1 tumor-bearing mice, in which antitumor immunity is remarkably amplified to inhibit tumor growth and metastasis.

Synthetic Topological Nodal Phase in Bilayer Resonant Gratings.

The notion of synthetic dimensions in artificial photonic systems has received considerable attention as it provides novel methods for exploring hypothetical topological phenomena as well as potential device applications. Here, we present nanophotonic manifestation of a two-dimensional topological nodal phase in bilayer resonant grating structures. Using the mathematical analogy between a topological semimetal and vertically asymmetric photonic lattices, we show that the interlayer shift simulates an extra momentum dimension for creating a two-dimensional topological nodal phase. We present a theoretical model and rigorous numerical analyses showing the two nodal points that produce a complex gapless band structure and localized edge states in the topologically nontrivial region. Therefore, our results provide a practical scheme for producing high-dimensional topological effects in simple low-dimensional photonic structures.

Recruitment of dendritic cells using 'find-me' signaling microparticles for personalized cancer immunotherapy.

Therapeutic cancer vaccines have attracted attention because of their potential to prime cytotoxic T cells, which are highly antigen (Ag)-specific, allowing personalized cancer immunotherapy. However, because of their low immunogenicity, cancer vaccines have been used in only a few types of cancers in clinics, primarily because of the poor Ag presentation of dendritic cells (DCs). To address these limitations of cancer vaccines, we show that 'find-me' signaling polymeric microparticles (F-PMs) bearing tumor lysate as an Ag can efficiently recruit DCs and facilitate antigen presentation. When subcutaneously injected into tumor-bearing mice, F-PMs significantly increased mature DCs in tumor-draining lymph nodes by eliciting adenosine triphosphate (ATP)-induced chemotaxis, resulting in high antitumor efficacy. CD8+ cytotoxic T cells were remarkably enriched in the tumor microenvironment following co-administration of an immune checkpoint inhibitor with F-PMs. We demonstrated that F-PMs elicit a robust antitumor immune response, which may provide a promising therapeutic option for cancer treatment.

Sulfisoxazole Elicits Robust Antitumour Immune Response Along with Immune Checkpoint Therapy by Inhibiting Exosomal PD-L1.

Despite their potent antitumor activity, clinical application of immune checkpoint inhibitors has been significantly limited by their poor response rates (<30%) in cancer patients, primarily due to immunosuppressive tumor microenvironments. As a representative immune escape mechanism, cancer-derived exosomes have recently been demonstrated to exhaust CD8+ cytotoxic T cells. Here, it is reported that sulfisoxazole, a sulfonamide antibacterial, significantly decreases the exosomal PD-L1 level in blood when orally administered to the tumor-bearing mice. Consequently, sulfisoxazole effectively reinvigorates exhausted T cells, thereby eliciting robust antitumor effects in combination with anti-PD-1 antibody. Overall, sulfisoxazole regulates immunosuppression through the inhibition of exosomal PD-L1, implying its potential to improve the response rate of anti-PD-1 antibodies.

Optical bench simulation for intraocular lenses using field-tracing technology.

PURPOSE: To evaluate the image quality of intraocular lenses (IOLs) using field-tracing optical simulation and then compare it with the image quality using conventional ray-tracing simulation. METHODS: We simulated aspheric IOLs with a decenter, tilt, and no misalignment using an aspheric corneal eye model with a positive spherical aberration. The retinal image, Strehl ratio, and modulation transfer function (MTF) were compared between the ray-tracing and field-tracing optical simulation and confirmed by the results reported in an in vitro experiment using the same eye model. RESULTS: The retinal image showed interference fringes from target due to diffraction from the object in a field-tracing simulation. When compared with the experimental results, the field tracing represented the experimental results more precisely than ray tracing after passing over 400 µm of the decentration and 4 degrees of the tilt of the IOLs. The MTF values showed similar results for the case of no IOL misalignment in both the field tracing and ray tracing. In the case of the 200-µm decentration or 8-degree tilt of IOL, the field-traced MTF shows lower values than the ray-traced one. CONCLUSIONS: The field-tracing optical bench simulation is a reliable method to evaluate IOL performance according to the IOL misalignment. It can provide retinal image quality close to real by taking into account the wave nature of light, interference and diffraction to explain to patients having the IOL misalignment.

Development of a novel multifocal lens using a polarization directed flat lens: possible candidate for a multifocal intraocular lens.

BACKGROUND: A polarization-directed flat (PDF) lens acts as a converging lens with a focal length (f) > 0 and a diverging lens with f < 0, depending on the polarization state of the incidental light. To produce a multifocal lens with two focal lengths, a PDF and a converging lens having shorter focal length were combined. In this study, we tested a bifocal PDF to determine its potential as a new multifocal intraocular lens (IOL). METHODS: Constructed a multifocal lens with a PDF lens (f = +/- 100 mm) and a converging lens (f = + 25 mm). In an optical bench test, we measured the defocus curve to test the multifocal function. The multifocal function and optical quality of the lens in various situations were tested. An Early Treatment Diabetic Retinopathy Study (ETDRS) chart as a near target and a building as a distant target were photographed using a digital single-lens reflex (DSLR) camera. Both lenses (multifocal and monofocal) were tested under the same conditions. RESULTS: For the 0 D and - 20 D focal points, the multifocal lens showed sharp images in the optical bench test. In the DSLR test using the multifocal lens, the building appeared slightly blurry compared with the results using the monofocal lens. With the multifocal lens, the ETDRS chart's images became blurry as the ETDRS chart's distance decreased, but became very clear again at a certain position. CONCLUSIONS: We confirmed the multifocal function of the multifocal lens using a PDF lens. This lens can be used as a multifocal IOL in the future.

Metabolically engineered stem cell-derived exosomes to regulate macrophage heterogeneity in rheumatoid arthritis.

Despite the remarkable advances in therapeutics for rheumatoid arthritis (RA), a large number of patients still lack effective countermeasures. Recently, the reprogramming of macrophages to an immunoregulatory phenotype has emerged as a promising therapeutic strategy for RA. Here, we report metabolically engineered exosomes that have been surface-modified for the targeted reprogramming of macrophages. Qualified exosomes were readily harvested from metabolically engineered stem cells by tangential flow filtration at a high yield while maintaining their innate immunomodulatory components. When systemically administered into mice with collagen-induced arthritis, these exosomes effectively accumulated in the inflamed joints, inducing a cascade of anti-inflammatory events via macrophage phenotype regulation. The level of therapeutic efficacy obtained with bare exosomes was achievable with the engineered exosomes of 10 times less dose. On the basis of the boosted nature to reprogram the synovial microenvironment, the engineered exosomes display considerable potential to be developed as a next-generation drug for RA.

All-solid-state spatial light modulator with independent phase and amplitude control for three-dimensional LiDAR applications.

Spatial light modulators are essential optical elements in applications that require the ability to regulate the amplitude, phase and polarization of light, such as digital holography, optical communications and biomedical imaging. With the push towards miniaturization of optical components, static metasurfaces are used as competent alternatives. These evolved to active metasurfaces in which light-wavefront manipulation can be done in a time-dependent fashion. The active metasurfaces reported so far, however, still show incomplete phase modulation (below 360°). Here we present an all-solid-state, electrically tunable and reflective metasurface array that can generate a specific phase or a continuous sweep between 0 and 360° at an estimated rate of 5.4 MHz while independently adjusting the amplitude. The metasurface features 550 individually addressable nanoresonators in a 250 × 250 µm2 area with no micromechanical elements or liquid crystals. A key feature of our design is the presence of two independent control parameters (top and bottom gate voltages) in each nanoresonator, which are used to adjust the real and imaginary parts of the reflection coefficient independently. To demonstrate this array's use in light detection and ranging, we performed a three-dimensional depth scan of an emulated street scene that consisted of a model car and a human figure up to a distance of 4.7 m.

Metasurface-driven OLED displays beyond 10,000 pixels per inch.

Optical metasurfaces are starting to find their way into integrated devices, where they can enhance and control the emission, modulation, dynamic shaping, and detection of light waves. In this study, we show that the architecture of organic light-emitting diode (OLED) displays can be completely reenvisioned through the introduction of nanopatterned metasurface mirrors. In the resulting meta-OLED displays, different metasurface patterns define red, green, and blue pixels and ensure optimized extraction of these colors from organic, white light emitters. This new architecture facilitates the creation of devices at the ultrahigh pixel densities (>10,000 pixels per inch) required in emerging display applications (for instance, augmented reality) that use scalable nanoimprint lithography. The fabricated pixels also offer twice the luminescence efficiency and superior color purity relative to standard color-filtered white OLEDs.

Metal-Phenolic Network-Coated Hyaluronic Acid Nanoparticles for pH-Responsive Drug Delivery.

Although self-assembled nanoparticles (SNPs) have been used extensively for targeted drug delivery, their clinical applications have been limited since most of the drugs are released into the blood before they reach their target site. In this study, metal-phenolic network (MPN)-coated SNPs (MPN-SNPs), which consist of an amphiphilic hyaluronic acid derivative, were prepared to be a pH-responsive nanocarrier to facilitate drug release in tumor microenvironments (TME). Due to their amphiphilic nature, SNPs were capable of encapsulating doxorubicin (DOX), chosen as the model anticancer drug. Tannic acid and FeCl3 were added to the surface of the DOX-SNPs, which allowed them to be readily coated with MPNs as the diffusion barrier. The pH-sensitive MPN corona allowed for a rapid release of DOX and effective cellular SNP uptake in the mildly acidic condition (pH 6.5) mimicking TME, to which the hyaluronic acid was exposed to facilitate receptor-mediated endocytosis. The DOX-loaded MPN-SNPs exhibited a higher cytotoxicity for the cancer cells, suggesting their potential use as a drug carrier in targeted cancer therapy.

Recent Advances in Polymeric Nanomedicines for Cancer Immunotherapy.

Immunotherapy has emerged as a promising approach to treat cancer, since it facilitates eradication of cancer by enhancing innate and/or adaptive immunity without using cytotoxic drugs. Of the immunotherapeutic approaches, significant clinical potentials are shown in cancer vaccination, immune checkpoint therapy, and adoptive cell transfer. Nevertheless, conventional immunotherapies often involve immune-related adverse effects, such as liver dysfunction, hypophysitis, type I diabetes, and neuropathy. In an attempt to address these issues, polymeric nanomedicines are extensively investigated in recent years. In this review, recent advances in polymeric nanomedicines for cancer immunotherapy are highlighted and thoroughly discussed in terms of 1) antigen presentation, 2) activation of antigen-presenting cells and T cells, and 3) promotion of effector cells. Also, the future perspectives to develop ideal nanomedicines for cancer immunotherapy are provided.