Water-Immiscible Coacervate as a Liquid Magnetic Robot for Intravascular Navigation.

Developing magnetic ultrasoft robots to navigate through extraordinarily narrow and confined spaces like capillaries in vivo requires synthesizing materials with excessive deformability, responsive actuation, and rapid adaptability, which are difficult to achieve with the current soft polymeric materials, such as elastomers and hydrogels. We report a magnetically actuatable and water-immiscible (MAWI) coacervate based on the assembled magnetic core-shell nanoparticles to function as a liquid robot. The degradable and biocompatible millimeter-sized MAWI coacervate liquid robot can remain stable under changing pH and salt concentrations, release loaded cargoes on demand, squeeze through an artificial capillary network within seconds, and realize intravascular targeting in vivo guided by an external magnetic field. We believe the proposed "coacervate-based liquid robot" can implement demanding tasks beyond the capability of conventional elastomer or hydrogel-based soft robots in the field of biomedicine and represents a distinct design strategy for high-performance ultrasoft robots.

Directed Conformational Switching of a Zinc Finger Analogue Regulates the Mechanosensing and Differentiation of Stem Cells.

The dynamic conformational changes in the secondary structures of proteins are essential to their functions and can regulate diverse cellular events. Herein we report the design of a synthetic polymer-based secondary structure analogue of a zinc finger (ZnF) by introducing a zinc coordination motif to overcome the free energy barrier predicted by theoretical calculations and fold-free polymer chains. The conformational switching between unfolded and folded state of the ZnF analogue can be triggered in situ to drastically manipulate the accessibility of conjugated cell adhesive ligands to the cell membrane receptors, thereby effectively controlling the adhesion, spreading, mechanosensing, and differentiation of stem cells. We believe that emulating the dynamic secondary structures of proteins via rational design of a folded synthetic polymer-cation complex is a promising strategy for developing bioactive materials to mediate desired cellular functions.

Anisotropic Ligand Nanogeometry Modulates the Adhesion and Polarization State of Macrophages.

Material implants trigger host reactions generated by cells, such as macrophages, which display dynamic adhesion and polarization including M1 inflammatory state and M2 anti-inflammatory state. Creating materials that enable diverse nanoscale display of integrin-binding groups, such as RGD ligand, can unravel nanoscale recruitment and ligation of integrin, which modulate cellular adhesion and activation. Here, we synthesized gold nanorods (GNRs) with various nanoscale anisotropies (i.e., aspect ratios, ARs), but in similar surface areas, and controlled their substrate conjugation to display an anisotropic ligand nanogeometry without modulating ligand density. Using nanoscale immunolabeling, we demonstrated that highly anisotropic ligand-coated GNRs ("AR4" and "AR7") facilitated the recruitment of integrin ß1 on macrophages to their nanoscale surfaces. Consequently, highly anisotropic GNRs (e.g., "AR4" and "AR7") elevated the adhesion and M2 state of macrophages, with the inhibition of their M1 state in the culture and mice, entailing rho-associated protein kinase. This nanoscale anisotropic nanogeometry provides a novel and critical parameter to be considered in the generation of biomaterials to potentially modulate host reactions to the implants for immunomodulatory tissue regeneration.

Bioadhesive Polymersome for Localized and Sustained Drug Delivery at Pathological Sites with Harsh Enzymatic and Fluidic Environment via Supramolecular Host-Guest Complexation.

Targeted and sustained delivery of drugs to diseased tissues/organs, where body fluid exchange and catabolic activity are substantial, is challenging due to the fast cleansing and degradation of the drugs by these harsh environmental factors. Herein, a multifunctional and bioadhesive polycaprolactone-ß-cyclodextrin (PCL-CD) polymersome is developed for localized and sustained co-delivery of hydrophilic and hydrophobic drug molecules. This PCL-CD polymersome affords multivalent crosslinking action via surface CD-mediated host-guest interactions to generate a supramolecular hydrogel that exhibits evident shear thinning and efficient self-healing behavior. The co-delivery of small molecule and proteinaceous agents by the encapsulated PCL-CD polymersomes enhances the differentiation of stem cells seeded in the hydrogel. Furthermore, the PCL-CD polymersomes are capable of in situ grafting to biological tissues via host-guest complexation between surface CD and native guest groups in the tissue matrix both in vitro and in vivo, thereby effectively extending the retention of loaded cargo in the grafted tissue. It is further demonstrated that the co-delivery of small molecule and proteinaceous drugs via PCL-CD polymersomes averts cartilage degeneration in animal osteoarthritic (OA) knee joints, which are known for their biochemically harsh and fluidically dynamic environment.

Hydrogels that mimic developmentally relevant matrix and N-cadherin interactions enhance MSC chondrogenesis.

Methacrylated hyaluronic acid (HA) hydrogels provide a backbone polymer with which mesenchymal stem cells (MSCs) can interact through several cell surface receptors that are expressed by MSCs, including CD44 and CD168. Previous studies showed that this 3D hydrogel environment supports the chondrogenesis of MSCs, and here we demonstrate through functional blockade that these specific cell-material interactions play a role in this process. Beyond matrix interactions, cadherin molecules, a family of transmembrane glycoproteins, play a critical role in tissue development during embryogenesis, and N-cadherin is a key factor in mediating cell-cell interactions during mesenchymal condensation and chondrogenesis. In this study, we functionalized HA hydrogels with N-cadherin mimetic peptides and evaluated their role in regulating chondrogenesis and cartilage matrix deposition by encapsulated MSCs. Our results show that conjugation of cadherin peptides onto HA hydrogels promotes both early chondrogenesis of MSCs and cartilage-specific matrix production with culture, compared with unmodified controls or those with inclusion of a scrambled peptide domain. This enhanced chondrogenesis was abolished via treatment with N-cadherin-specific antibodies, confirming the contribution of these N-cadherin peptides to chondrogenesis. Subcutaneous implantation of MSC-seeded constructs also showed superior neocartilage formation in implants functionalized with N-cadherin mimetic peptides compared with controls. This study demonstrates the inherent biologic activity of HA-based hydrogels, as well as the promise of biofunctionalizing HA hydrogels to emulate the complexity of the natural cell microenvironment during embryogenesis, particularly in stem cell-based cartilage regeneration.

A gold@polydopamine core-shell nanoprobe for long-term intracellular detection of microRNAs in differentiating stem cells.

The capability of monitoring the differentiation process in living stem cells is crucial to the understanding of stem cell biology and the practical application of stem-cell-based therapies, yet conventional methods for the analysis of biomarkers related to differentiation require a large number of cells as well as cell lysis. Such requirements lead to the unavoidable loss of cell sources and preclude real-time monitoring of cellular events. In this work, we report the detection of microRNAs (miRNAs) in living human mesenchymal stem cells (hMSCs) by using polydopamine-coated gold nanoparticles (Au@PDA NPs). The PDA shell facilitates the immobilization of fluorescently labeled hairpin DNA strands (hpDNAs) that can recognize specific miRNA targets. The gold core and PDA shell quench the fluorescence of the immobilized hpDNAs, and subsequent binding of the hpDNAs to the target miRNAs leads to their dissociation from Au@PDA NPs and the recovery of fluorescence signals. Remarkably, these Au@PDA-hpDNA nanoprobes can naturally enter stem cells, which are known for their poor transfection efficiency, without the aid of transfection agents. Upon cellular uptake of these nanoprobes, we observe intense and time-dependent fluorescence responses from two important osteogenic marker miRNAs, namely, miR-29b and miR-31, only in hMSCs undergoing osteogenic differentiation and living primary osteoblasts but not in undifferentiated hMSCs and 3T3 fibroblasts. Strikingly, our nanoprobes can afford long-term tracking of miRNAs (5 days) in the differentiating hMSCs without the need of continuously replenishing cell culture medium with fresh nanoprobes. Our results demonstrate the capability of our Au@PDA-hpDNA nanoprobes for monitoring the differentiation status of hMSCs (i.e., differentiating versus undifferentiated) via the detection of specific miRNAs in living stem cells. Our nanoprobes show great promise in the investigation of the long-term dynamics of stem cell differentiation, identification and isolation of specific cell types, and high-throughput drug screening.

Biomimetic Hydrogels as the Inductive Endochondral Ossification Template for Promoting Bone Regeneration.

Repairing critical size bone defects (CSBD) is a major clinical challenge and requires effective intervention by biomaterial scaffolds. Inspired by the fact that the cartilaginous template-based endochondral ossification (ECO) process is crucial to bone healing and development, developing biomimetic biomaterials to promote ECO is recognized as a promising approach for repairing CSBD. With the unique highly hydrated 3D polymeric network, hydrogels can be designed to closely emulate the physiochemical properties of cartilage matrix to facilitate ECO. In this review, the various preparation methods of hydrogels possessing the specific physiochemical properties required for promoting ECO are introduced. The materiobiological impacts of the physicochemical properties of hydrogels, such as mechanical properties, topographical structures and chemical compositions on ECO, and the associated molecular mechanisms related to the BMP, Wnt, TGF-ß, HIF-1α, FGF, and RhoA signaling pathways are further summarized. This review provides a detailed coverage on the materiobiological insights required for the design and preparation of hydrogel-based biomaterials to facilitate bone regeneration.

Coacervation-Mediated Cytocompatible Formation of Supramolecular Hydrogels with Self-Evolving Macropores for 3D Multicellular Spheroid Culture.

Coacervation driven liquid-liquid phase separation of biopolymers has aroused considerable attention for diverse applications, especially for the construction of microstructured polymeric materials. Herein, a coacervate-to-hydrogel transition strategy is developed to create macroporous hydrogels (MPH), which are formed via the coacervation process of supramolecular assemblies (SA) built by the host-guest complexation between γ-cyclodextrin and anthracene dimer. The weak and reversible supramolecular crosslinks endow the SA with liquid-like rheological properties, which facilitate the formation of SA-derived macroporous coacervates and the subsequent transition to MPH (pore size ≈ 100 µm). The excellent structural dynamics (derived from SA) and the cytocompatible void-forming process of MPH can better accommodate the dramatic volumetric expansion associated with colony growth of encapsulated multicellular spheroids compared with the non-porous static hydrogel with similar initial mechanical properties. The findings of this work not only provide valuable guidance to the design of biomaterials with self-evolving structures but also present a promising strategy for 3D multicellular spheroid culture and other diverse biomedical applications.

Dynamic gelatin-based hydrogels promote the proliferation and self-renewal of embryonic stem cells in long-term 3D culture.

Long-term maintenance of embryonic stem cells (ESCs) in the undifferentiated state is still challenging. Compared with traditional 2D culture methods, 3D culture in biomaterials such as hydrogels is expected to better support the long-term self-renewal of ESCs by emulating the biophysical and biochemical properties of the extracellular matrix (ECM). Although prior studies showed that soft and degradable hydrogels favor the 3D growth of ESCs, few studies have examined the impact of the structural dynamics of the hydrogel matrix on ESC behaviors. Herein, we report a gelatin-based structurally dynamic hydrogel (GelCD hydrogel) that emulates the intrinsic structural dynamics of the ECM. Compared with covalently crosslinked gelatin hydrogels (GelMA hydrogels) with similar stiffness and biodegradability, GelCD hydrogels significantly promote the clonal expansion and viability of encapsulated mouse ESCs (mESCs) independent of MMP-mediated hydrogel degradation. Furthermore, GelCD hydrogels better maintain the pluripotency of encapsulated mESCs than do traditional 2D culture methods that use MEF feeder cells or medium supplementation with GSK3ß and MEK 1/2 inhibitors (2i). When cultured in GelCD hydrogels for an extended period (over 2 months) with cell passaging every 7 days, mESCs preserve their normal morphology and maintain their pluripotency and full differentiation capability. Our findings highlight the critical role of the structural dynamics of the hydrogel matrix in accommodating the volume expansion that occurs during clonal ESC growth, and we believe that our dynamic hydrogels represent a valuable tool to support the long-term 3D culture of ESCs.

Biomaterial-mediated presentation of wnt5a mimetic ligands enhances chondrogenesis and metabolism of stem cells by activating non-canonical Wnt signaling.

The presentation of development-relevant bioactive cues by biomaterial scaffolds is essential to the guided differentiation of seeded human mesenchymal stem cells (hMSCs) and subsequent tissue regeneration. Wnt5a is a critical non-canonical Wnt signaling ligand and plays a key role in the development of musculoskeletal tissues including cartilage. Herein we investigate the efficacy of biofunctionalizing the hyaluronic acid hydrogel with a synthetic Wnt5a mimetic ligand (Foxy5 peptide) to promote the chondrogenesis of hMSCs and the potential underlying molecular mechanism. Our findings show that the conjugation of Foxy5 peptide in the hydrogels activates non-canonical Wnt signaling of encapsulated hMSCs via the upregulation expression of PLCE1, CaMKII-ß, and downstream NFATc1, leading to enhanced expression of chondrogenic markers such as SOX9. The decoration of Foxy5 peptide also promotes the metabolic activities of encapsulated hMSCs as evidenced by upregulated gene expression of mitochondrial complex components and glucose metabolism biomarkers, leading to enhanced ATP biosynthesis. Furthermore, the conjugation of Foxy5 peptide activates the non-canonical Wnt, PI3K-PDK-AKT and IKK/NF-κB signaling pathways, thereby inhibiting the hypertrophy of the chondrogenically induced hMSCs in the hydrogels under both in vitro and in vivo conditions. This enhanced chondrogenesis and attenuated hypertrophy of hMSCs by the biomaterial-mediated bioactive cue presentation facilitates the potential clinical translation of hMSCs for cartilage regeneration. Our work provides valuable guidance to the rational design of bio-inductive scaffolds for various applications in regenerative medicine.

Biomaterial-Mediated Presentation of Jagged-1 Mimetic Ligand Enhances Cellular Activation of Notch Signaling and Bone Regeneration.

The development from stem cells to adult tissues requires the delicate presentation of numerous crucial inductive cues and the activation of associated signaling pathways. The Notch signaling pathways triggered by ligands such as Jagged-1 have been demonstrated to be essential in various development processes especially in osteogenesis and ossification. However, few studies have capitalized on the osteoinductivity of the Jagged-1 mimetic ligands to enhance the osteogenesis and skeleton regeneration. In this study, we conjugate the porous hyaluronic acid hydrogels with a Jagged-1 mimetic peptide ligand (Jagged-1) and investigate the efficacy of such biomimetic functionalization to promote the mechanotransduction and osteogenesis of human mesenchymal stem cells by activating the Notch signaling pathway. Our findings indicate that the immobilized Jagged-1 mimetic ligand activates Notch signaling via the upregulation of NICD and downstream MSX2, leading to the enhanced mechanotransduction and osteogenesis of stem cells. We further demonstrate that the functionalization of the Jagged-1 ligand in the porous scaffold promotes angiogenesis, regulates macrophage recruitment and polarization, and enhances in situ regeneration of rat calvarial defects. Our findings provide valuable guidance to the design of development-inspired bioactive biomaterials for diverse biomedical applications.

Magnesium-Encapsulated Injectable Hydrogel and 3D-Engineered Polycaprolactone Conduit Facilitate Peripheral Nerve Regeneration.

Peripheral nerve injury is a challenging orthopedic condition that can be treated by autograft transplantation, a gold standard treatment in the current clinical setting. Nevertheless, limited availability of autografts and potential morbidities in donors hampers its widespread application. Bioactive scaffold-based tissue engineering is a promising strategy to promote nerve regeneration. Additionally, magnesium (Mg) ions enhance nerve regeneration; however, an effectively controlled delivery vehicle is necessary to optimize their in vivo therapeutic effects. Herein, a bisphosphonate-based injectable hydrogel exhibiting sustained Mg2+ delivery for peripheral nerve regeneration is developed. It is observed that Mg2+ promoted neurite outgrowth in a concentration-dependent manner by activating the PI3K/Akt signaling pathway and Sema5b. Moreover, implantation of polycaprolactone (PCL) conduits filled with Mg2+ -releasing hydrogel in 10 mm nerve defects in rats significantly enhanced axon regeneration and remyelination at 12 weeks post-operation compared to the controls (blank conduits or conduits filled with Mg2+ -absent hydrogel). Functional recovery analysis reveals enhanced reinnervation in the animals treated with the Mg2+ -releasing hydrogel compared to that in the control groups. In summary, the Mg2+ -releasing hydrogel combined with the 3D-engineered PCL conduit promotes peripheral nerve regeneration and functional recovery. Thus, a new strategy to facilitate the repair of challenging peripheral nerve injuries is proposed.

Injectable chitin hydrogels with self-healing property and biodegradability as stem cell carriers.

To meet the demands of various therapeutic tasks, injectable hydrogels with tunable mechanical properties and degradability are highly desired. Herein, we developed an injectable chitin hydrogel system with well-manipulated mechanical properties and degradability through dynamic acylhydrazone crosslinking catalyzed by 4-amino-DL-phenylalanine (Phe-NH2). The mechanical properties and degradability of the hydrogels could be easily adjusted by varying the solid content, while their gelation time could be maintained at a constant level (∼130 s) by altering Phe-NH2 content, thereby ensuring the good injectability of hydrogels. Moreover, the chitin hydrogels showed excellent self-healing capacity with a healing efficiency up to 95 %. Owing to their superior biocompatibility and biodegradability, the chitin hydrogels could support the proliferation and multi-potent differentiations of rat bone marrow-derived stem cells, serving as a beneficial 3D scaffold for stem cell encapsulation and delivery. This work provides a promising injectable delivery vehicle of therapeutic drugs or cells for tissue regenerative medicine.

Nanoparticle-Assembled Vacuolated Coacervates Control Macromolecule Spatiotemporal Distribution to Provide a Stable Segregated Cell Microenvironment.

Membraneless coacervate compartments in the intracellular and pericellular space mediate critical cellular functions. Developing synthetic coacervates that emulate the morphological, physical, and functional complexity of these natural coacervates is challenging but highly desirable. Herein, a generalizable nanoparticle assembly (NPA) strategy is developed, which is applicable to interactive core-shell nanoparticles with different chemical makeups, to fabricate vacuolated coacervates. The obtained NPA coacervates contain stable internal vacuoles to provide segregated microcompartments, which can mediate the spatially heterogeneous distribution of diverse macromolecules via restricted diffusion. It is further shown that the vacuolated NPA coacervates can harbor and retain macromolecular medium supplements to regulate the functions of cells encapsulated in vacuoles. Furthermore, the restricted macromolecule diffusion can be abolished on demand via the triggered coacervate-hydrogel transition, thereby altering the exposure of encapsulated cells to environmental factors. It is believed that the NPA strategy provides new insights into the design principles of hierarchical coacervates that hold promising potential for a wide array of biomedical applications.

Enhanced mechanosensing of cells in synthetic 3D matrix with controlled biophysical dynamics.

3D culture of cells in designer biomaterial matrices provides a biomimetic cellular microenvironment and can yield critical insights into cellular behaviours not available from conventional 2D cultures. Hydrogels with dynamic properties, achieved by incorporating either degradable structural components or reversible dynamic crosslinks, enable efficient cell adaptation of the matrix and support associated cellular functions. Herein we demonstrate that given similar equilibrium binding constants, hydrogels containing dynamic crosslinks with a large dissociation rate constant enable cell force-induced network reorganization, which results in rapid stellate spreading, assembly, mechanosensing, and differentiation of encapsulated stem cells when compared to similar hydrogels containing dynamic crosslinks with a low dissociation rate constant. Furthermore, the static and precise conjugation of cell adhesive ligands to the hydrogel subnetwork connected by such fast-dissociating crosslinks is also required for ultra-rapid stellate spreading (within 18 h post-encapsulation) and enhanced mechanosensing of stem cells in 3D. This work reveals the correlation between microscopic cell behaviours and the molecular level binding kinetics in hydrogel networks. Our findings provide valuable guidance to the design and evaluation of supramolecular biomaterials with cell-adaptable properties for studying cells in 3D cultures.

Long-Term Detection of Oncogenic MicroRNA in Living Human Cancer Cells by Gold@ Polydopamine-Shell Nanoprobe.

Oncogenic microRNAs (miRNA), for example, miR-155, are key tumor biomarkers in cancer cells that drive tumorigenesis, and the miRNA profile signature can predict cancer development and aggressiveness. Hence, timely detection of oncogenic miRNA in living cells is highly attractive to the diagnosis of cancer at an early stage. Herein, we report a highly sequence-specific gold@polydopamine-based nanoprobe for long-term detection of miRNA in human cancer cell lines in vitro. A single administration of the nanoprobe enables continuous detection of the miR-155 expression level in living cancer cells for up to 5 days. We believe that our nanoprobe is highly promising for both oncology research and translational applications.

Biocompatible cellulose-based supramolecular nanoparticles driven by host-guest interactions for drug delivery.

To extend the applications of natural products in nanomedicine, novel cellulose-based supramolecular nanoparticles (SNPs) were fabricated via a host-guest driven self-assembly strategy here. The adamantane-grafted carboxyethyl hydroxyethyl cellulose and ß-cyclodextrin-grafted glycerol ethoxylate were synthesized to self-assemble into the SNPs. Furthermore, doxorubicin (DOX)-functionalized ß-cyclodextrin was encapsulated into SNPs via an in situ co-assembly process to generate DOX-loaded SNPs (DOX-SNPs). The SNPs exhibited a quasi-spherical morphology with an average diameter of ∼25 nm. The DOX-SNPs with relatively larger diameter possessed a high DOX loading efficiency (∼94 %) and the pH-responsive drug release behaviors, which made them suitable as a drug delivery system. In vitro cytotoxicity assays demonstrated the excellent cytocompatibility of SNPs and the efficient inhibition of Hela cell proliferation of DOX-SNPs. Moreover, the DOX-SNPs could effectively enter Hela cells via endocytosis and release DOX under endo/lysosome pH. Thus, this nanocarrier has promising translational potential in cancer therapy and personalized nanomedicine.

Biomimetic Presentation of Cryptic Ligands via Single-Chain Nanogels for Synergistic Regulation of Stem Cells.

Dynamic controlling the nanoscale presentation of synergistic ligands to stem cells by biomimetic single-chain materials can provide critical insights to understand the molecular crosstalk underlying cells and their extracellular matrix. Here, a stimuli-responsive single-chain macromolecular nanoregulator with conformational dynamics is fabricated based on an advanced scale-up single polymeric chain nanogel (SCNG). Such a carefully designed SCNG is capable of mediating a triggered copresentation of the master and cryptic ligands in a single molecule to elicit the synergistic crosstalk between different intracellular signaling pathways, thereby considerably boosting the bioactivity of the presented ligands. This controllable nanoswitching-on of cell-adhesive ligands' presentation allows the regulation of cell adhesion and fate from molecular scale. The modular nature of this synthetic macromolecular nanoregulator makes it a versatile nanomaterial platform to assist basic and fundamental studies in a wide array of research topics.

Organic semiconducting polymer amphiphile for near-infrared-II light-triggered phototheranostics.

Development of near-infrared-II (NIR-II) light responsive nano-agents with high photothermal stability, high photothermal conversion efficiency (PCE), and excellent biocompatibility for photoacoustic (PA) imaging-guided photothermal therapy (PTT) is of tremendous significance. In spite of the superiority of organic semiconducting polymer nanoparticles (OSPNs) in PA imaging-guided PTT, the limited absorption in the first NIR (NIR-I) window and metastable nanostructure of OSPNs resulting from commonly used preparation methods based on nanoprecipitation or reprecipitation compromise their in vivo phototheranostic performance. Herein we design and synthesize a novel NIR-II absorbing organic semiconducting polymer amphiphile (OSPA) to enhance the structural stability of OSPNs. With prominent optical properties, low toxicity, and a suitable size, OSPA not only efficiently labels and kills cancer cells under NIR-II irradiation but also accumulates at the tumor of living mice upon intravenous injection, allowing efficient NIR-II light-triggered phototheranostics toward tumor. The developed OSPA has promising potential for fabricating multifunctional nanoplatforms to enable multimodal theranostics.

Effective Phototheranostics of Brain Tumor Assisted by Near-Infrared-II Light-Responsive Semiconducting Polymer Nanoparticles.

Precise diagnosis and effective treatment of gliomas still remain a huge challenge. Photoacoustic-guided photothermal therapy (PTT) has unique advantages over conventional techniques for brain tumor theranostics, but existing nanoagents for photoacoustic imaging (PAI)-guided PTT are mainly organic small molecules or inorganic nanoparticles, which have the limitations of poor photostability and biocompatibility. Besides, the restricted absorption in the first near-infrared window (NIR-I) of the most existing nanoagents compromises their effectiveness for deep tissue PAI and PTT. We herein develop novel semiconducting polymer nanoparticles (SPNs) that are strongly absorptive in the second NIR window (NIR-II) to alleviate these problems. With the merits of excellent photoacoustic and photothermal performance, high photostability, proper size, and low toxicity, SPNs not only show efficient cellular uptake for PAI and PTT toward U87 glioma cells but also demonstrate effective accumulation in both subcutaneous tumors and brain tumors upon intravenous injection, thereby realizing efficient PAI-guided PTT toward gliomas under NIR-II light irradiation.