Abstract Patient-derived xenograft (PDX) models represent a milestone of preclinical oncology research, serving as a valuable in vivo system for evaluating drug efficacy in mice and informing potential personalized therapeutic strategies. However, widespread application of PDX models has been limited by prolonged and variable engraftment timelines, relatively low success rates, and substantial operational costs. Moreover, the gradual replacement of human tumor microenvironment (TME) with murine stromal components compromises the fidelity of PDX models, particularly for evaluating immunomodulatory agents, which requires an intact human immune context. While patient-derived organoids (PDOs) offer a faster and more efficient modeling alternative, their utility is limited by absence of a representative TME, difficulties in assay standardization, and inherent selection bias towards specific cancer cell clones. These limitations raise concerns regarding their ability to provide reliable prediction on efficacy to complex treatment regimens, thereby motivating the development of more holistic ex vivo approaches. In the current study, we established an ex vivo tissue culture platform utilizing freshly resected patient tumors to evaluate anti-tumor efficacy of test articles across a panel of patient tumors. Tumor samples obtained from surgery were processed immediately into uniform sections by tissue slicing and cultured in a trans-well system exposed to various stimulants and/or test articles. Post incubation, the cultured tumor tissues were subjected to multiple downstream analyses, including tumor killing assessment, immune cell profiling, biomarker analysis, immunohistochemistry (IHC) and immunofluorescence (IF). The culture medium was analyzed to profile secreted cytokines and chemokines. An illustrative application: tumor tissues collected from lung cancer patients were evaluated on this platform to compare anti-PD1 responses. Tumor collected from anti-PD1 responsive patient revealed pronounced tumor suppression characterized by a 25% increase in CD8+CD103+ T cells and a 22% reduction in CD163+ macrophages by flow cytometry, enhanced caspase-3 staining, decreased Ki-67 and TGF-β signals via IF, and elevated expression levels of cytokines associated with immune suppression and TAM recruitment as measured by Luminex, collectively distinguishing this profile from that of non-responders. This ex vivo tissue culture system dramatically expands the utility of clinical specimens while maintaining native architecture and cellular heterogeneity. It enables rapid and direct assessment of therapeutic responses and shows strong correlation with in vivo outcomes, bridging a critical gap between traditional in vitro assays and subsequent in vivo studies. This approach may accelerate the pipeline for anti-cancer drug discovery and development. Citation Format: Jie Wen, Hao Cheng, Nan Yang. A patient-derived ex vivo platform for personalized evaluation of both direct and immune-mediated drug responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 656.

Despite the high sensitivity of triple-negative breast cancer (TNBC) to tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) therapy, its efficacy was limited by rapid systemic clearance and treatment tolerance. To overcome these barriers, we developed a pH-responsive nanoparticle-to-hydrogel system for long-lasting retention of TRAIL receptors at the tumour site and promoting apoptosis in TRAIL-sensitive TNBC cells. The nanoparticle core, composed of soluble TRAIL (sTRAIL) and terpyridine (TPY), was assembled via silk fibroin self-polymerization, while a metal-polyphenol (MPN) complexation structure imparts a pH-responsive outer shell. After peritumoral injection, the slightly acidic tumour microenvironment transiently degraded MPN, releasing dihydromyricetin (DMY) to upregulate the TRAIL receptor DR5, whereas Fe3+ covalently bound TPY, triggering nanoparticle-to-gel conversion. The system achieved a high DMY loading via the MPN network, rapidly released DMY under acidic tumour microenvironment conditions, and induced apoptotic receptor DR5 upregulation within 24 h. Dynamic covalent bond reconstitution converted nanoparticles into a hydrogel in situ, forming a stable library for sustained TRAIL release. Compared with conventional gels, this sequential fast-activation and continuous synergistic apoptosis strategy minimized burst release, extended TRAIL activity beyond six days, and localized the drug to the lesion area, increasing the local concentration of the drug while reducing systemic exposure. In vitro and in vivo studies confirmed enhanced apoptosis through dual-drug synergy with minimal systemic toxicity. This dynamic switching strategy delivery offers an innovative platform for protein-small molecule co-therapy, addressing TNBC resistance, and holds translational potential for clinical applications.

Therapeutic proteins play a crucial role in modern healthcare. However, the rapid clearance of proteins in the circulation system poses a significant threat to their therapeutic efficacy. The generation of anti-drug antibodies expedites drug clearance, resulting in another challenge to overcome in protein delivery. Several methods to increase the circulation half-lives of these proteins and to minimize their immunogenicity have been developed. This Review discusses the causes of protein clearance in the body, evaluates the FDA-approved strategies to prolong protein circulation, and highlights recent progress in the field. Additionally, the strengths and drawbacks of these methods and our perspectives for advancing protein delivery are provided.

Highly crystalline two-dimensional (2D) flakes of birnessite, a polymorph of manganese oxide with a MnO2 chemistry, were synthesized by reacting manganese oxide, Mn3O4, at 80 degrees C with aqueous solutions of tetramethylammonium hydroxide (TMAH) for tens of hours. Their colloidal stability, aggregation, and sedimentation were studied as a function of ionic strengths of Na+ and Li+ cations. After reaction, a water-based stable colloidal suspension (zeta-potential similar to -31 +/- 1 mV) was obtained. Mixing the colloidal suspension with a LiCl or NaCl aqueous solution resulted in the sedimentation of crumpled flakes, as evidenced by electron microscopy (transmission and scanning). Concomitant with the sedimentation, the TMA+ cations present after synthesis are exchanged by the alkali ions, as evidenced by a decrease in the d-spacings between the 2D sheets illustrated by X-ray diffraction (XRD). Both Na and Li uptakes were quantified by elemental analysis via inductively coupled plasma tandem mass spectrometry, giving Li0.17Mn0.96O2 and Na0.16Mn0.96O2. Rhodamine 6G dye was also studied as a sedimentation agent, resulting in a maximum uptake of 550 mg (1.15 mmol) of dye per g of birnessite. To explore the immune response of the Li+-intercalated crumpled flakes, the activation of antigen-presenting cells by the flakes was investigated. It was found that the immune cells were slightly activated in a dose-dependent manner, indicating that the materials may have good biocompatibility and thus possibe applications in healthcare.

O2-dependent photodynamic therapy (PDT) represents an efficient strategy for tumor ablation, but its therapeutic efficacy is critically compromised in hypoxic tumors. To tackle unsatisfying O2 supplying, we design a dual-nanoparticle assembly for O2 source-carrying photosensitizer delivery to enhance PDT efficiency. Structurally, catalase (CAT) is condensed into nanocapsules for biostability and sustainable O2 supplying, and indocyanine green (ICG) is dispersed in polymeric nanospheres to prevent photobleaching and self-aggregation. According to O2 demands, CAT nanocapsules are covalently conjugated with ICG nanospheres in an optimal ratio to facilitate O2 enrichment around photosensitizer, together with hyaluronic acid (HA) decoration for advanced tumor targeting, thereby achieving O2-autarky PDT in hypoxic tumors. In comparison to simply-mixed delivery of CAT nanocapsules and ICG nanospheres, dual-nanoparticle assembly enables co-accumulation of CAT and ICG at the tumor site via HA receptor recognition, followed by CAT-catalyzed O2-generation and in situ O2-supplying to the surrounded ICG nanospheres, thereby satisfying O2 demands of hypoxic tumors during PDT. Consequently, the nanoassembly significantly increases the intra-tumoral oxyhemoglobin saturation to 31.68% and yields tumor inhibition of 85.94% in the orthotopic breast cancer models. Collectively, this study provides a dualnanoparticle assembly design of O2 source-carrying photosensitizer to achieve O2-autarky PDT and establishes a new paradigm for O2-dependent PDT in hypoxic tumors.

STING1 is a central hub protein of CGAS-STING1 signaling which is important signaling axis to sense DNA for the host against pathogens infection through regulating type I interferon (IFN-I) production. However, excessive STING1 activation-induced overproduced IFN-I triggers tissue damage and autoimmune disorders. Thus, the activity of STING1 must be precisely regulated for immune homeostasis. Here, we discovered SESN1 (sestrin 1) as an essential negative regulator of STING1 to maintain immune homeostasis. Upon herpes simplex virus-1 (HSV-1) infection, the expression of SESN1 was downregulated, which enhanced potentiality to virus defense for host. Consistently, SESN1-deficient mice exhibited stronger ability against HSV-1 infection compared to wild-type littermates. Additionally, we found the expression of SESN1 was decreased in systemic lupus erythematosus (SLE) patients and trex1 KO mouse model of autoimmune disease. Intriguingly, the replenishment of SESN1 effectively impressed IFN-I production and autoimmune responses in the PBMCs of human SLE specimens and the trex1 KO mouse model both in vitro and in vivo. Mechanistically, SESN1 targeted STING1 and promoted STING1 autophagic degradation by facilitating the interaction of SQSTM1/p62 and STING1. Together, our study uncovers a crucial role of SESN1 for immune homeostasis to balance anti-virus and autoimmunity by regulating STING1. SESN1 might be a potential therapeutic target for infectious and autoimmune diseases.Abbreviations: BMDMs: bone marrow-derived macrophages; cGAMP: cyclic GMP-AMP; CGAS: cyclic GMP-AMP synthase; HTDNA: herring testes DNA; IFNA4: interferon alpha 4; IFNB: interferon beta; IRF3: interferon regulatory factor 3; ISD: interferon stimulatory DNA; ISGs: IFN-stimulated genes; PBMCs: peripheral blood mononuclear cells; RSAD2: radical S-adenosyl methionine domain containing 2; SLE: systemic lupus erythematosus; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1.

Mesenchymal stem cell (MSC) therapy holds promise in biomedical applications but faces challenges in efficient transfection without compromising cell viability. Here, we show a serum-tolerant MSC transfection nanotool, APOs@BP, composed of an apolipoprotein (APO) corona and a boronated polyethyleneimine (BP) core. The APOs corona's serum-protein resistance and cytomembrane affinity enable APOs@BP to achieve 10.4-fold higher transfection efficiency and improved cytocompatibility in serum-containing medium compared to high-molecular-weight polycationic transfectants. For MSC neural differentiation, miRNA-124 and all-trans retinoic acid derivative (atRAN) are further loaded into APOs@BP, forming a polymeric complex for sequential drug release triggered by lysosomal acid and cytosolic reactive oxygen species post-transplantation. Transcriptomic analysis confirms that this system enhances MSC neural differentiation through sequential activation of atRAN-induced differentiation potential and miRNA-124-directed neurogenesis via cGMP-PKG, MAPK, and PI3K-Akt pathways. Transplantation of engineered MSCs reconstructs neural circuits and alleviates cognitive impairment in Alzheimer's disease model mice. Collectively, this system provides a robust and convenient method for MSC-based regenerative medicine.

Type 1 diabetes (T1D) is an autoimmune disorder in which pancreatic β-cells are destroyed by CD8+ T cells. Anti-CD3 antibody effectively treats early-stage T1D when β-cell autoantibodies are detected but before symptoms appear. However, it impairs the immune system temporarily, exposing individuals to infection. A therapeutic that can reverse new-onset T1D without harming the immune system remains urgently needed. Herein, we have constructed cellular vesicles presenting granzyme B-responsive fusion proteins (designated aCD8-GrzBcs-IL2) composed of a single-chain variable fragment of anti-CD8 antibodies and a mutein interleukin-2 (IL2). aCD8-GrzBcs-IL2 is designed to simultaneously inhibit CD8+ T cells and promote Treg cells, especially when CD8+ T cells are attacking β-cells. In vitro, these cellular vesicles can inhibit the cell-killing effect of CD8+ T cells and enhance the expansion of Treg cells. Notably, intravenous administration of aCD8-GrzBcs-IL2-expressed cellular vesicles reversed newly onset diabetes in 77.8% of nonobese diabetic (NOD) mice without reducing blood CD3+ T cells and CD8+ T cells, indicating a favorable safety profile.

Tumor-specific apoptosis exerts considerable curative efficacy in cancer, particularly with TRAIL, which has been approved in the clinic; however, therapeutic outcome is compromised due to apoptosis evasion and the short half-life of exogenously infused TRAIL. Herein, we propose a synergistic apoptosis strategy of orthotopic TRAIL expression for enhancing the bystander effect and mitochondrial photodamage for intrinsic apoptosis activation. To actualize synergetic apoptosis, we develop cascade-targeting nanoparticles to perform cell-to-mitochondria shuttling, in which TRAIL-expressing plasmid (pTRAIL) is coprecipitated with calcium phosphate on a glycyrrhetinic acid (GA)-modified graphene oxide nanosheet. For apoptosis synergy, GA mediates tumor accumulation of nanoparticles, followed by structure dissociation for efficient pTRAIL release and expression (cascade module I). Thereafter, GA-modified graphene carriers perform mitochondria distribution for laser-triggered photodamage (cascade module II). The nanoparticles yield tumor inhibition of 86.78% in the melanoma model and demonstrate metastasis blocking activity. Collectively, a cascade-targeting apoptosis technology via a combination of TRAIL-specific bystander effects and mitochondrial photodamage provides innovative oncotherapy synergy.

The tumor microenvironment (TME) emerges as a unique challenge to oncotherapy due to its intricate ecosystem containing diverse cell types, extracellular matrix, secreted factors, and neovascularization, which furnish tumor growth, progression, invasion, and metastasis. Graphene oxide (GO)-based materials have garnered increasing attention in cancer therapy owing to their vast specific surface area, flexible lamellar structure, and electronic-photonic properties. Recently, interactions of GO with the TME have been broadly investigated, including trapping biomolecules, catalysis, cancer stem cell targeting, immunoreactions, etc., which inspires combinative therapeutic strategies to overcome TME obstacles. Herein, we summarize TME features, GO modulating various dimensions of the TME, and a TME-triggerable drug delivery system and highlight innovation and merits in combinative cancer therapy based on TME modulation. This review aims to offer researchers deeper insights into the interactions between versatile GO nanomaterials and the TME, facilitating the development of rational and reliable GO-based nanomedicines for advanced oncotherapy.

Abstract Antibody therapeutics has been proven clinically against various cancer types and have achieved great success. Majority of the therapeutic antibodies target cell surface or extracellular proteins. Most of the tumor-specific antigens that control cell growth, proliferation, and death are intracellular, and traditional antibody therapies fail to recognize intracellular antigen targets. Such tumor specific intracellular targets consist of overexpressed self antigens, oncofetal protein, cancer testis antigens, viral protein and neo-antigens of mutant proteins. Recently, an emerging approach to target these neo-epitopes has been developed called T-cell receptor-like/TCR-mimic antibodies as they recognize similar epitopes to those of T cell receptors which target specific peptide-MHC complexes(pMHC). TCR mimic antibodies open a new avenue for targeting intracellular antigens yet there are lots of challenges for generating highly selective and potent TCR mimic antibodies. MAGE-A4, melanoma-associated antigen A4, is a member of the MAGE protein family of cancer-testis antigen (CTA). In healthy adult, MAGE-A4 expression is restricted to immune-privileged sites. But MAGE-A4 is widely expressed on many cancers such as lung cancer, head and neck squamous cell cancer, synovial sarcoma(SS), ovarian cancer, urothelial cancer and melanoma. The decapeptide GVYDGREHTV(amino acids 230-239) derived from MAGE-A4, can be presented by HLA-A*02:01 molecule, elicits specific cytotoxicity T cell response. Afami-cel, a genetically modified autologous T cell therapy against this pMHC complex, showed promising potency for patients with metastatic SS. So MAGE-A4/HLA-A*02:01 may be a good target for TCR mimic antibodies and cancer immunotherapy. In the present study, we utilized a newly established single cell cloning platform LyTARS to generate TCR mimic antibodies against HLA restricted MAGE-A4 peptide. Recombinant HLA-A*02:01 MAGE-A4 protein was used to immunize mice and plasma B cells from immunized mice were sorted and loaded onto LyTARS system. Clones that showed reactivity to recombinant HLA-A*02:01 MAGE-A4 but not to irrelevant pMHC (WT-1) were exported and sequenced. Purified antibodies were extensively characterized by the specificity, affinity, and potency by ADCC. Results demonstrated that the TCR mimic antibodies identified have sub-nano molar affinity by protein based ELISA, bind to peptide pulsed T2 cells that endogenously expressing HLA with nano-Molar apparent affinity. TCR mimic antibodies also demonstrated antibody dependent cell killing with the potency of sub-nanomolar. In summary, we have generated and extensively characterized a panel of high affinity and selective TCR mimic antibodies against HLA-A*02:01 MAGE-A4 using a newly established single cell cloning platform. Citation Format: Hao Cheng, You Wu, Tianfeng Shi, Yang Yu, Min Wang, Chenjun Jia, Wenfang Xin, Hu Liu, Teddy Yang, Danmei Yao. Discovery of T cell receptor mimic antibody against MAGE-A4 with single B-cell cloning platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3194.

AbstractHypervascularized glioblastoma is naturally sensitive to anti‐angiogenesis but suffers from low efficacy of transient vasculature normalization. In this study, a lipid‐polymer nanoparticle is synthesized to execute compartmentalized Cas9 and sgRNA delivery for a permanent vasculature editing strategy by knocking out the signal transducer and activator of transcription 3 (STAT3). The phenylboronic acid branched cationic polymer is designed to condense sgRNA electrostatically (inner compartment) and patch Cas9 coordinatively (outer compartment), followed by liposomal hybridization with angiopep‐2 decoration for blood–brain barrier (BBB) penetration. The lipid‐polymer nanoparticles can reach glioblastoma within 2 h post intravenous administration, and hypoxia in tumor cells triggers charge‐elimination and degradation of the cationic polymer for burst release of Cas9 and sgRNA, accompanied by instant Cas9 RNP assembly, yielding ≈50% STAT3 knockout. The downregulation of downstream vascular endothelial growth factor (VEGF) reprograms vasculature normalization to improve immune infiltration, collaborating with interleukin‐6 (IL‐6) and interleukin‐10 (IL‐10) reduction to develop anti‐glioblastoma responses. Collectively, the combinational assembly for compartmentalized Cas9/sgRNA delivery provides a potential solution in glioblastoma therapy.

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The clinical advancement of protein-based nanomedicine has revolutionized medical professionals' perspectives on cancer therapy. Protein-based nanoparticles have been exploited as attractive vehicles for cancer nanomedicine due to their unique properties derived from naturally biomacromolecules with superior biocompatibility and pharmaceutical features. Furthermore, the successful translation of Abraxane™ (paclitaxel-based albumin nanoparticles) into clinical application opened a new avenue for protein-based cancer nanomedicine. In this mini-review article, we demonstrate the rational design and recent progress of protein-based nanoparticles along with their applications in cancer diagnosis and therapy from recent literature. The current challenges and hurdles that hinder clinical application of protein-based nanoparticles are highlighted. Finally, future perspectives for translating protein-based nanoparticles into clinic are identified.

Collaboration of cancerous cells and microenvironment is the root for tumor spreading, leading to difficulty in complete metastasis blockage via mono-intervention. Herein, a triple-responsive nanoassembly is designed for orienting tumor cells and migration-driving M2 tumor associated macrophages (TAMs) in microenvironment for efficient anti-metastatic therapy. Structurally, a reactive oxygen species (ROS)-responsive crosslinked short-chain polyquaternium is synthesized to bridge graphene oxide (GO) scaffold with apolipoprotein A-I crown via borate-crosslinking, electrostatic adherence, and coordinative coupling. The protein-crowning polymeric GO nanoparticles could give multimodal shielding and triple-responsive release of doxorubicin and Snail-targeted siRNA. Tailor-made apolipoprotein A-I crown fulfills nanoparticles synergistically attacking tumor cells and M2 TAMs via binding with overexpressed scavenger receptors. The findings witness the targeted accumulation and potent cytotoxicity of the hybrid nanoparticles for M2 TAMs and tumor cells; especially, elimination of M2 TAMs in tumor microenvironment holds back Snail-enhancing transforming growth factor (TGF)-β signal pathway, which collaborates with Snail silencing in tumor cells to reverse epithelial mesenchymal transition (EMT) and metastasis-promoting niche. Collectively, the synergistic targeting therapeutic platform could provide a promising solution for metastatic tumor treatment.

Considering the thermal environment’s effect, we built a dynamics model of rotating pre-twisted ceramic matrix composites blades with elastic boundary constraints based on shell and first-order shear deformation theories. The model considers the effect of temperature and simplifies the blade to a twisted cylindrical plate. Based on the Lagrange equation, the differential equation of the vibration of a rotating pre-twisted blade of CNTs-reinforced ceramic matrix composites in the thermal environment was derived by using the orthogonal polynomial as the acceptable function. The natural frequencies and vibration modes of a rotating pre-twisted blade take into account the effects of Coriolis and centrifugal forces. The accuracy of the model is verified by comparing with the literature and Ansys results. The effects of temperature, the volume fraction of functional gradient, pre-twisted angle, and rotational speed on the model were studied in detail. The results show that the addition of carbon nanotubes can greatly enhance the ceramic-based blade. And both temperature and pre-twisted angle significantly affect the carbon nanotube enhanced functional gradient blades.

Supplementary Methods, Figures 1-6 from Induction of Cancer Cell Death by Self-assembling Nanostructures Incorporating a Cytotoxic Peptide

Perovskite of superior photocatalysis renders attractive potential in photodynamic therapy (PDT), but compromise in biomedical applications due to intrinsic susceptible hydrolysis and safety concerns. Here, a trilaminar-structured, hyaluronidase-responsive pro-photosensitizer (HMT) is fabricated by perovskite (MASnI3)-titanium dioxide (TiO2)-hyaluronic acid (HA) ploygel passivator for advanced cytoplasm-specific sustainable PDT. Structurally, an efficient electron-hole transfer medium of TiO2 was deposited onto MASnI3 for hydrolysis-resistance, which could give robust hydroxyl radical production in hypoxia. The HMT is passivated by HA-gel clicking for bio-stabilization, tumor-specific penetration and cellular internalization. The HA-corona detachment by hyaluronidase in tumor triggers revitalization of photoinduced-hydrogen-abstraction, promising instant ROS generation. After topical administration, HMT induces complete tumor elimination via mitochondria damage upon multi-cycle NIR irradiation. Moreover, no side-effect is noted in toxicity study, potentially profiting from topical application, tumor targeting and minimized dosage by multi-cycle irradiation. Collectively, we herein propose a pioneering perovskite photosensitizer for non-oxygen dependent PDT.

The human immune system is an interaction network of biological processes, and its dysfunction is closely associated with a wide array of diseases, such as cancer, infectious diseases, tissue damage, and autoimmune diseases. Manipulation of the immune response network in a desired and controlled fashion has been regarded as a promising strategy for maximizing immunotherapeutic efficacy and minimizing side effects. Integration of "smart" bioresponsive materials with immunoactive agents including small molecules, biomacromolecules, and cells can achieve on-demand release of agents at targeted sites to reduce overdose-related toxicity and alleviate off-target effects. This review highlights the design principles of bioresponsive immunotherapeutic materials and discusses the critical roles of controlled release of immunoactive agents from bioresponsive materials in recruiting, housing, and manipulating immune cells for evoking desired immune responses. Challenges and future directions from the perspective of clinical translation are also discussed.

Polydopamine (PDA) is capable of wide drug delivery for biomedical applications by virtue of an adjustable polymerization process, including surface coating and conjugation. Inspired by the polymerization of dopamine, we introduce a layer-by-layer hybrid co-assembly strategy for the incorporation of doxorubicin (DOX) and dopamine to form PDA "carrier-drug" hybrid assembly. The "carrier-drug" hybrid assembly relies on the π-π stacking interaction between the drug (DOX) and carrier (PDA), and such the stacked-layer structure enables PDA nanoparticles with a superior drug loading of 58%, which is about 1.7-fold higher than that of the DOX surface coating (∼35%). To further improve blood circulation stability and enhance tumor penetration, we herein propose the conjugation of native apolipoprotein A-I (apoA-I) with tumor-homing cyclic peptide iRGD for PDA surface modification. The "carrier-drug" hybrid assembly can respond to triple stimuli of the acidic pH, concentrated reactive oxygen species (ROS), and near-infrared (NIR) light irradiation for realizing site-specific and on-demand drug release. In chemo-photothermal synergy therapy, the "carrier-drug" hybrid assembly performs efficient tumor penetration and accumulation, dramatically suppressing tumor growth and metastasis in a 4T1 orthotopic tumor-bearing mice model at a safe level. Collectively, our findings share new insights into the design of "carrier-drug" hybrid assembly for enhanced chemo-photothermal oncotherapy.