A Biodegradable Nanosuspension Locally Used for Inhibiting Postoperative Recurrence and Brain Metastasis of Breast Cancer.

Addressing the urgent need to prevent breast cancer postoperative recurrence and brain metastasis, Fe-metal organic framework (MOF)-coated hollow mesoporous organosilica nanoparticles (HMON) with tumor microenvironment dual-responsive degradability were prepared to encapsulate doxorubicin (DOX), formulating a tissue-adhesive nanosuspension for perioperative topical medication. This nanosuspension can not only retain the sustainably released drug in the postoperative residual tumor sites but also enhance the intracellular oxidative stress of tumors for remarkable tumor ferroptosis. Interestingly, the nanosuspension can act as an immune amplifier, which could not only stimulate DC cells to secrete chemokines for T cell recruitment but also elevate antigen exposure to facilitate the antigen presentation in lymph nodes. Thus, this nanosuspension could significantly activate antitumor immune responses in both in situ tumors and metastatic encephaloma for enhanced immunotherapy. In conjunction with the clinical PD-1 antibody, the locally administered nanosuspension could achieve an advanced therapeutic outcome for inhibiting postoperative recurrence and metastasis.

Retraction: An MSN-PEG-IP drug delivery system and IL13Rα2 as targeted therapy for glioma.

Retraction of 'An MSN-PEG-IP drug delivery system and IL13Rα2 as targeted therapy for glioma' by Jinlong Shi et al., Nanoscale, 2017, 9, 8970-8981, https://doi.org/10.1039/C6NR08786H.

Cell Membrane Perforation: Patterns, Mechanisms and Functions.

Cell membrane is crucial for the cellular activities, and any disruption to it may affect the cells. It is demonstrated that cell membrane perforation is associated with some biological processes like programmed cell death (PCD) and infection of pathogens. Specific developments make it a promising technique to perforate the cell membrane controllably and precisely. The pores on the cell membrane provide direct pathways for the entry and exit of substances, and can also cause cell death, which means reasonable utilization of cell membrane perforation is able to assist intracellular delivery, eliminate diseased or cancerous cells, and bring about other benefits. This review classifies the patterns of cell membrane perforation based on the mechanisms into 1) physical patterns, 2) biological patterns, and 3) chemical patterns, introduces the characterization methods and then summarizes the functions according to the characteristics of reversible and irreversible pores, with the aim of providing a comprehensive summary of the knowledge related to cell membrane perforation and enlightening broad applications in biomedical science.

Recent Developments in CaCO3 Nano-Drug Delivery Systems: Advancing Biomedicine in Tumor Diagnosis and Treatment.

Calcium carbonate (CaCO3), a natural common inorganic material with good biocompatibility, low toxicity, pH sensitivity, and low cost, has a widespread use in the pharmaceutical and chemical industries. In recent years, an increasing number of CaCO3-based nano-drug delivery systems have been developed. CaCO3 as a drug carrier and the utilization of CaCO3 as an efficient Ca2+ and CO2 donor have played a critical role in tumor diagnosis and treatment and have been explored in increasing depth and breadth. Starting from the CaCO3-based nano-drug delivery system, this paper systematically reviews the preparation of CaCO3 nanoparticles and the mechanisms of CaCO3-based therapeutic effects in the internal and external tumor environments and summarizes the latest advances in the application of CaCO3-based nano-drug delivery systems in tumor therapy. In view of the good biocompatibility and in vivo therapeutic mechanisms, they are expected to become an advancing biomedicine in the field of tumor diagnosis and treatment.

Transcriptome Data Revealed the circRNA-miRNA-mRNA Regulatory Network during the Proliferation and Differentiation of Myoblasts in Shitou Goose.

CircRNA, a recently characterized non-coding RNA (ncRNA) variant, functions as a molecular sponge, exerting regulatory control by binding to microRNA (miRNA) and modulating the expression of downstream proteins, either promoting or inhibiting their expression. Among poultry species, geese hold significant importance, prized by consumers for their delectable taste and rich nutritional content. Despite the prominence of geese, research on the growth and development of goose muscle, particularly the regulatory role of circRNAs in goose muscle formation, remains insufficiently explored. In this study, we constructed comprehensive expression profiles of circRNAs and messenger RNAs (mRNAs) within the myoblasts and myotubes of Shitou geese. We identified a total of 96 differentially expressed circRNAs (DEcircRNAs) and 880 differentially expressed mRNAs (DEmRNAs). Notably, the parental genes of DEcircRNAs and DEmRNAs exhibited enrichment in the Wnt signaling pathway, highlighting its potential impact on the proliferation and differentiation of goose myoblasts. Employing RNAhybrid and miRDB, we identified circRNA-miRNA pairs and mRNA-miRNA pairs that may play a role in regulating myogenic differentiation or muscle growth. Subsequently, utilizing Cytoscape, we constructed a circRNA-miRNA-mRNA interaction network aimed at unraveling the intricate regulatory mechanisms involved in goose muscle growth and development, which comprises 93 circRNAs, 351 miRNAs, and 305 mRNAs. Moreover, the identification of 10 hub genes (ACTB, ACTN1, BDNF, PDGFRA, MYL1, EFNA5, MYSM1, THBS1, ITGA8, and ELN) potentially linked to myogenesis, along with the exploration of their circRNA-miRNA-hub gene regulatory axis, was also conducted. These competitive endogenous RNA (ceRNA) regulatory networks elucidate the molecular regulatory mechanisms associated with muscle growth in Shitou geese, providing deeper insights into the reciprocal regulation of circRNA, miRNA, and mRNA in the context of goose muscle formation.

Receptor-Targeted Carbon Nanodot Delivery through Polymer Caging and Click Chemistry-Supported LRP1 Ligand Attachment.

Carbon nanodots present resistance to photobleaching, bright photoluminescence, and superior biocompatibility, making them highly promising for bioimaging applications. Herein, nanoprobes were caged with four-armed oligomers and subsequently modified with a novel DBCO-PEG-modified retro-enantio peptide ligand reL57, enhancing cellular uptake into U87MG glioma cells highly expressing low-density lipoprotein receptor-related protein 1 (LRP1). A key point in the development of the oligomers was the incorporation of ε-amino-linked lysines instead of standard α-amino-linked lysines, which considerably extended the contour length per monomer. The four-armed oligomer 1696 was identified as the best performer, spanning a contour length of ~8.42 nm for each arm, and was based on an altering motive of two cationic ε-amidated lysine tripeptides and two tyrosine tripeptides for electrostatic and aromatic stabilization of the resulting formulations, cysteines for disulfide-based caging, and N-terminal azidolysines for click-modification. This work highlights that well-designed four-armed oligomers can be used for noncovalent coating and covalent caging of nanoprobes, and click modification using a novel LRP1-directed peptide ligand facilitates delivery into receptor-expressing target cells.

Covalent organic frameworks: linkage types, synthetic methods and bio-related applications.

Covalent organic frameworks (COFs) are composed of small organic molecules linked via covalent bonds, which have tunable mesoporous structure, good biocompatibility and functional diversities. These excellent properties make COFs a promising candidate for constructing biomedical nanoplatforms and provide ample opportunities for nanomedicine development. A systematic review of the linkage types and synthesis methods of COFs is of indispensable value for their biomedical applications. In this review, we first summarize the types of various linkages of COFs and their corresponding properties. Then, we highlight the reaction temperature, solvent and reaction time required by different synthesis methods and show the most suitable synthesis method by comparing the merits and demerits of various methods. To appreciate the cutting-edge research on COFs in bioscience technology, we also summarize the bio-related applications of COFs, including drug delivery, tumor therapy, bioimaging, biosensing and antimicrobial applications. We hope to provide insight into the interdisciplinary research on COFs and promote the development of COF nanomaterials for biomedical applications and their future clinical translations.

In Situ Attached Photothermal Immunomodulation-Enhanced Nanozyme for the Inhibition of Postoperative Malignant Glioma Recurrence.

Glioblastoma (GBM) is one of the most challenging malignant brain tumors to treat. Herein, we describe a nanoenzyme hemostatic matrix strategy with the tumor cavity in situ application that simultaneously serves as photothermal agent and induces immunogenic cell death after GBM surgical resection to enhance the antitumor immunity and delay tumor recurrence. The hemostatic matrix system (Surgiflo@PCN) contains Surgiflo, a multispace structure that can be used to penetrate different shapes of tumor cavities to prevent postoperative tumor cavity hemorrhage. As well, porous palladium-copper nanoclusters (PCNs) have adjustable enzyme-like activities (oxidase, peroxidase, and catalase) responsible for formation of reactive oxygen species (ROS) under near-infrared (808 nm) laser irradiation. When the Surgiflo@PCN entered the resected tumor cavity, the first action was the direct killing of glioma cells via ROS and photothermal therapy (PTT). The second action was the induction of immunogenic cell death by PCN-enhanced oxidative stress and PTT, which reversed the immunosuppressive tumor microenvironment and enhanced the antitumor immune response. This eradicated residual glioma cells and prevented recurrence. The collective findings demonstrate that Surgiflo@PCN kills glioma cells directly through ROS and PTT and enhances antiglioma immunity and kills glioma cells indirectly. The "one-stone, two-birds" strategy could become an effective photothermal immunotherapy in GBM patients.

CircPLXNA2 Affects the Proliferation and Apoptosis of Myoblast through circPLXNA2/gga-miR-12207-5P/MDM4 Axis.

CircRNAs are newly identified special endogenous RNA molecules that covalently close a loop by back-splicing with pre-mRNA. In the cytoplasm, circRNAs would act as molecular sponges to bind with specific miRNA to promote the expression of target genes. However, knowledge of circRNA functional alternation in skeletal myogenesis is still in its infancy. In this study, we identified a circRNA-miRNA-mRNA interaction network in which the axis may be implicated in the progression of chicken primary myoblasts' (CPMs) myogenesis by multi-omics (i.e., circRNA-seq and ribo-seq). In total, 314 circRNA-miRNA-mRNA regulatory axes containing 66 circRNAs, 70 miRNAs, and 24 mRNAs that may be relevant to myogenesis were collected. With these, the circPLXNA2-gga-miR-12207-5P-MDM4 axis aroused our research interest. The circPLXNA2 is highly differentially expressed during differentiation versus proliferation. It was demonstrated that circPLXNA2 inhibited the process of apoptosis while at the same time stimulating cell proliferation. Furthermore, we demonstrated that circPLXNA2 could inhibit the repression of gga-miR-12207-5p to MDM4 by directing binding to gga-miR-12207-5p, thereby restoring MDM4 expression. In conclusion, circPLXNA2 could function as a competing endogenous RNA (ceRNA) to recover the function of MDM4 by directing binding to gga-miR-12207-5p, thereby regulating the myogenesis.

Antioxidant Cascade Nanoenzyme Antagonize Inflammatory Pain by Modulating MAPK/p-65 Signaling Pathway.

Chronic pain has attracted wide interest because it is a major obstacle affecting the quality of life. Consequently, safe, efficient, and low-addictive drugs are highly desirable. Nanoparticles (NPs) with robust anti-oxidative stress and anti-inflammatory properties possess therapeutic possibilities for inflammatory pain. Herein, a bioactive zeolitic imidazolate framework (ZIF)-8-capped superoxide dismutase (SOD) and Fe3 O4 NPs (SOD&Fe3 O4 @ZIF-8, SFZ) is developed to achieve enhanced catalytic, antioxidative activities, and inflammatory environment selectivity, ultimately improving analgesic efficacy. SFZ NPs reduce tert-butyl hydroperoxide (t-BOOH)-induced reactive oxygen species (ROS) overproduction, thereby depressing the oxidative stress and inhibiting the lipopolysaccharide (LPS)-induced inflammatory response in microglia. After intrathecal injection, SFZ NPs efficiently accumulate at the lumbar enlargement of the spinal cord and significantly relieve complete Freund's adjuvant (CFA)-induced inflammatory pain in mice. Moreover, the detailed mechanism of inflammatory pain therapy via SFZ NPs is further studied, where SFZ NPs inhibit the activation of the mitogen-activated protein kinase (MAPK)/p-65 signaling pathway, leading to reductions in phosphorylated protein levels (p-65, p-ERK, p-JNK, and p-p38) and inflammatory factors (tumor necrosis factor [TNF]-α, interleukin [IL]-6, and IL-1ß), thereby preventing microglia and astrocyte activation for acesodyne. This study provides a new cascade nanoenzyme for antioxidant treatments and explores its potential applications as non-opioid analgesics.

Diabetes immunity-modulated multifunctional hydrogel with cascade enzyme catalytic activity for bacterial wound treatment.

Diabetes immunity-modulated wound treatment in response to the varied microenvironments at different stages remains an urgent challenge. Herein, glucose oxidase (GOx) and quasi-amorphous Fe2O3 are co-incorporated into Zn-MOF nanoparticle (F-GZ) for cascade enzyme catalytic activities, where not only the high blood glucose in the wound is consumed via the GOx catalysis, but also the effective anti-bacteria is achieved via the degradedly released Zn2+ synergistically with the catalytically produced ·OH during the bacterial infection period with the low pH microenvironment. Simultaneously, the reactive oxygen species scavenging and hypoxia relief is realized via catalyzing H2O2 to produce O2 at the relatively elevated pH environment during the wound recovery period. Subsequently, a multifunctional hydrogel with injectable, self-healing and hemostasis abilities, as well as uniformed F-GZ loading is prepared via the copolymerization reaction. This hydrogel behaves as F-GZ but reduces the toxic effects, which thus accelerates the diabetic wound healing. More importantly, this hydrogel is found to modulate the diabetes immunity possibly mediated via the released Zn2+, which thus contributes to the recovered pancreatic islet functions with improved glucose tolerance and increased insulin secretion for enhanced diabetic wound treatments. This work initiates a new strategy for simultaneous diabetic wound management and also suggests a potential way for diabetic immunity modulation.

Sensitive CTC analysis and dual-mode MRI/FL diagnosis based on a magnetic core-shell aptasensor.

Synergizing the sensitive circulating tumor cell (CTC) capture, detection, release and the specific magnetic resonance/fluorescence (MR/FL) imaging for accurate cancer diagnosis is of great importance for cancer treatment. Herein, EcoR1-responsive complementary pairing of two ssDNA with a fluorescent P0 aptamer, which can specifically bind with the overexpressed MUC1 protein on cancer cells, was covalently modified to SiO2@C-coated magnetic nanoparticles for preparing a special nanoparticle-mediated FL turn-on aptasensor (FSC-D-P0). This aptasensor can selectively capture/enrich CTC and thus achieve sensitive CTC detection/imaging in even the blood due to its stable targeting, unique magnetic properties and the regulated interactions between the quencher and the fluorescent groups. Meanwhile, FSC-D-P0 can release the captured CTC for further downstream analysis upon the EcoR1 enzyme-triggered cleavage of the double-stranded DNA (dsDNA). Most importantly, this aptasensor can distinctly avoid false positivity of MRI via multiple targeting mechanisms. Thus, the sensitive CTC capture, detection, release and accurate MR/FL imaging were synergistically combined into a single platform with good biocompatibility, promising a robust pattern for clinical tumor diagnosis in vitro and in vivo.

Targeted peptide-modified oxidized mesoporous carbon nanospheres for chemo-thermo combined therapy of ovarian cancer in vitro.

Ovarian cancer remains one of serious hazards to human health due to many drawbacks of existing available treatment options. In this study, a multifunctional chemo-thermo combined therapy nanoplatform (OMCNPID) was successfully prepared, which is composed of I6P8 peptide as a targeting moiety to interleukin-6 receptors (IL-6Rs), oxidized mesoporous carbon nanospheres (OMCN) as a near infrared (NIR)-triggered drug carrier and doxorubicin (DOX) as a chemotherapeutic drug and fluorescent agent. The synthesized multifunctional nanoplatform displayed high storage capacity for drugs and excellent photothermal properties. Besides, DOX was rapidly released from OMCNPID at the condition of low pH and NIR laser irradiation due to the dissociation of DOX from graphitic cores of OMCN. In vitro experimental results verified that OMCNPID could be markedly taken up by SKOV-3 monolayer cells and tumor spheroids, and revealed a remarkable synergistic chemo-photothermal effect against ovarian cancer. All the results demonstrated that OMCNPID is a pH/NIR dual-stimulus responsive nanoplatform and can achieve efficient chemo-thermo combined therapy.

A Space-Time Conversion Vehicle for Programmed Multi-Drugs Delivery into Pancreatic Tumor to Overcome Matrix and Reflux Barriers.

The numerous biological barriers, which limit pharmacotherapy of pancreatic carcinoma, including inadequate drug accumulation in the tumor environment, a dense extracellular matrix (ECM) and efficient drug-efflux mechanisms, illustrate the requirement of multifunctional delivery systems to overcome the individual barriers at the right place at the right time. Herein, a space-time conversion vehicle based on covalent organic framework (COF)-coated mesoporous silica nanospheres (MSN) with a sandwiched polyethyleneimine (PEI) layer (MPCP), is designed. The space-specific drugs-loaded vehicle (MG PP CL P) is obtained by separately incorporating a chemotherapeutic agent (gemcitabine, G) into the MSN core, a P glycoprotein inhibitor (LY 335979, P) into the PEI layer, and an extracellular matrix disruptor (losartan, L) into the COF shell. Thereafter, a programmed drug delivery is achieved via the ordered degradation from COF shell to MSN core. Sequential release of the individual drugs, synergized with a change of nanoparticle surface charge, contribute to an obvious extracellular matrix distraction, distinct drug efflux inhibition, and consequently enhance chemotherapeutic outcomes in pancreatic carcinoma. This MPCP-based vehicle design suggests a robust space-time conversion strategy to achieve programmed multi-drugs delivery and represents a new avenue to the treatment of pancreatic carcinoma by overcoming extracellular matrix and drug reflux barriers.

Magnetic covalent organic framework nanospheres-based miRNA biosensor for sensitive glioma detection.

Sensitive detection and accurate diagnosis/prognosis of glioma remain urgent challenges. Herein, dispersed magnetic covalent organic framework nanospheres (MCOF) with uniformed Fe3O4 nano-assembly as cores and high-crystalline COF as shells were prepared by monomer-mediated in-situ interface growth strategy. Based on the unique interaction between MCOF and hairpin DNA, a fluorescent signal amplified miRNA biosensor was constructed. It could realize the sensitive detection of miRNA-182 in different matrixes, where the detection limit, linearity range and determination coefficient (R2) in real blood samples reached 20 fM, 0.1 pM-10 pM and 0.991, respectively. Also, it possessed good stability and precision as observed from the low intra-day/inter-day RSD and high extraction recovery. As a result, it could quantify miRNA-182 in serum of glioma patients, the concentration of which was significantly higher than that of healthy people and obviously decreased after surgery. Finally, a proof-of-concept capillary chip system using this biosensor was proposed to realize the visualized detection of miRNA-182 in microsample. These findings suggest a robust way for sensitive detection and accurate diagnosis/prognosis of glioma.

Tumor-Targeted Fluorescence Imaging and Mechanisms of Tumor Cell-Derived Carbon Nanodots.

An ideal cancer diagnostic probe should possess precise tumor-targeted accumulation with negligible sojourn in normal tissues. Herein, tumor cell-derived carbon nanodots (C-CNDU87 and C-CNDHepG2) about 3~7 nm were prepared by a solvothermal method with stable fluorescence and negligible cytotoxicity. More interestingly, due to the differences in gene expression of cancers, C-CND structurally mimicked the corresponding precursors during carbonization in which carbon nanodots were functionalized with α-amino and carboxyl groups with different densities on their edges. With inherent homology and homing effect, C-CND were highly enriched in precursor tumor tissues. Mechanistic studies showed that under the mediation of the original configuration of α-amino and carboxyl groups, C-CND specifically bound to the large neutral amino acid transporter 1 (LAT1, overexpressed in cancer cells), achieving specific tumor fluorescence imaging. This work provided a new vision about tumor cell architecture-mimicked carbon nanodots for tumor-targeted fluorescence imaging.

Mitochondrial Dysfunction and Antioxidation Dyshomeostasis-Enhanced Tumor Starvation Synergistic Chemotherapy Achieved using a Metal-Organic Framework-Based Nano-Enzyme Reactor.

Exploiting zeolitic imidazolate framework (ZIF)-based nanoparticles to synergistically enhance starvation-combined chemotherapy strategies remains an urgent demand. Herein, glucose oxidase (GOX) and doxorubicin (DOX) were facilely incorporated into ZIFs for starvation-combined chemotherapy. The as-prepared DOX/GOX-loaded ZIF (DGZ) exhibited uniform size with good dispersity, effective protection of the GOX activity, and stable delivery of the drugs into tumor. Correspondingly, it could achieve the glucose- and pH-responsive degradation and thus the controllable drug release. As a result, the acidification of glucose accompanied with reactive oxygen species (ROS) production was observed for the starvation-enhanced chemotherapy and the improved degradation. Most importantly, adjustable Zn2+ release was achieved with the biodegradation of DGZ, which thus contributed to an augmented therapeutic outcome via the Zn2+-induced mitochondrial dysfunction and antioxidation dyshomeostasis. These findings, synergized with the enhancement of starvation-combined chemotherapy by inhibiting the mitochondrial energy metabolism and boosting the ROS accumulation using pristine ZIF-based nanoparticles, provide a new insight into the metal-organic framework-based nanomedicine for further cancer treatments.

Tumor-Selective Biodegradation-Regulated Photothermal H2 S Donor for Redox Dyshomeostasis- and Glycolysis Disorder-Enhanced Theranostics.

H2 S-mediated tumor therapy has received great attention due to its unique physiological activity and synergistical enhancement, but suffers from limited H2 S donors with promised biosafety to regulate the H2 S delivery and subsequently the elusive pathway to augment the combined therapy. Herein, a PEGylated porous molybdenum disulfide nanoflower (MSP) with abundant defects is facilely synthesized for tumor-targeted theranostics. MSP possesses good water-dispersity and high photothermal ability, which is used for photoacoustic imaging and photothermal therapy. Interestingly, MSP is selectively degraded upon exposure to superfluous glutathione (GSH) within tumor cells, the mechanism of which is investigated, as a reduction-coordination reaction. This special degradation induces redox dyshomeostasis via GSH depletion for reactive oxygen species-accumulated chemodynamic therapy. Meanwhile, the selective biodegradation of MSP regulates a sustained H2 S release within tumor and achieves a targeted H2 S gas therapy via enhancing the glycolysis to acidify the tumor cells (glycolysis disorder). Synergistically, these performances are further enhanced via near-infrared photothermal heating, where excellent therapeutic outcomes with good biosafety are accomplished in vitro and in vivo. These characteristics, together with the unique biodegradation and no obvious side-effects of the nanoparticles, suggest a potential therapeutic strategy for precise tumor treatments.

A Novel Chemiluminescence Probe for Sensitive Detection of Fibroblast Activation Protein-Alpha In Vitro and in Living Systems.

Fibroblast activation protein-alpha (FAPα) is a key modulator of the microenvironment in multiple pathologies and is becoming the next pan-cancer target for cancer diagnostics and therapeutics. Chemiluminescence (CL) luminophores are considered as one of the most sensitive families of probes for detection and imaging applications due to their high signal-to-noise ratio. Until now, however, no such effective CL probe was reported for FAPα detection. Herein, we developed a novel CL probe for the detection of endogenous FAPα activity by incorporating FAPα-specific dipeptide substrates (glycine-proline) to the improved Schaap's adamantylidene-dioxetane. In this manner, we designed three CL probes (CFCL, BFCL, and QFCL) with the dipeptide substrate blocked by N-terminal benzyloxycarbonyl, N-tert-butoxycarbonyl or N-quinoline-4-carboxylic acid, respectively, which was used as the masking group to restrain the chemiexcitation energy. Probe CFCL exhibited the optimal specificity for the discrimination of FAPα from dipeptidase IV and prolyl oligopeptidase, which was elucidated by molecular docking simulation. Upon FAPα cleavage, CFCL was turned on for the highly selective and sensitive detection of FAPα with a limit of detection of 0.785 ng/mL. Furthermore, the ability of CFCL to image FAPα was effectively demonstrated in vitro, including various biological samples (plasma and tissue preparations), and in living systems (tumor cells and tumor-bearing mice). Furthermore, this newly established probe could be easily extended to evaluate FAPα inhibitors. Overall, we anticipate that probe CFCL will offer a facile and cost-effective alternative in the early detection of pathologies, individual tailoring of drug therapy, and drug screening.

Versatile hollow COF nanospheres via manipulating transferrin corona for precise glioma-targeted drug delivery.

Covalent organic framework (COF) nanoparticles for interference-free targeted drug delivery to glioma remains in its infancy. Herein, hollow COF nanospheres with high crystallinity and uniformed sizes were facilely prepared via heterogeneous nucleation-growth. The prepared COF had large surface area/pore volume and exhibited appropriate degradation behavior under acid environment, where therefore doxorubicin was effectively encapsulated and exhibited a pH-sensitive release. Most charmingly, T10 peptide that has high affinity with transferrin (Tf), was conjugated to endow the hollow COF interesting properties to specifically absorb Tf in vivo as Tf corona. For the first time, multifunctional hollow COF nanospheres (the better one named DCPT-2) were successfully synthesized to achieve interference-free cascade-targeting glioma drug delivery across the blood-brain barrier. Treatment with DCPT-2 brought an improved therapeutic outcome with significantly prolonged median survival time and low side effects. This work promised not only a potential protein corona-mediated COF-based drug delivery platform with good biocompatibility for effective and precise brain tumor therapy, but also an endogenous protein corona-mediated targeting strategy for general cancer therapy.