D-type neuropeptide decorated AIEgen/RENP hybrid nanoprobes with light-driven ROS generation ability for NIR-Ⅱ fluorescence imaging-guided through-skull photodynamic therapy of gliomas

Glioma is one of the most common malignant tumors of the central nervous system,leading high mortality rates in human.Aggregation-induced emission(AIE)photosensitizers-based photodynamic therapy(PDT)has emerged as a promising therapeutic strategy for least-invasive treatment of glioma,which involves local irradiation of the tumor using an external near-infrared(NIR)laser.Unfortunately,most AIE photosensitizers suffered from poorly penetration of the visible light excitation,bad spatiotemporal resolution in deep tissues and low efficient blood-brain barrier(BBB)crossing ability,which greatly limited the clinical practice of AIE photosensitizers for especially deep-seated brain tumor treatment.In this work,we developed a multifunctional NIR-driven theranostic agent through hybrid of AIE photosensitizers TIND with rare-earth doping nanoparticles(RENPs)NaGdF4:Nd/Yb/Tm with up/down dual-mode conversion luminescence.The theranostic agent was further decorated with D-type neuropeptide DNPY for crossing BBB and targeting glioma.Under the 808-nm light irradiation,the down-conversion NIR-II luminescence could indicate the position glioma and the upconversion NIR-I luminescence could trigger the AIE photosensitizers producing reactive oxygen species to inhibit orthotopic glioma tumor growth in situ.These results demonstrate that the integration of Dtype neuropeptide,AIE photosensitizers and RENPs could be promising candidates for in vivo NIR-II fluorescence image-guided through-skull PDT treatments of brain tumors.

Matthew effect:General design strategy of ultra-fluorogenic nanoprobes with amplified dark–bright states in aggregates

Fluorescence imaging,a key technique in biological research,frequently utilizes fluorogenic probes for precise imaging in living systems.Tetrazine is an effective emission quencher in fluorogenic probe designs,which can be selectively damaged upon bioorthogonal click reactions,leading to considerable emission enhancement.Despite significant efforts to increase the emission enhancement ratio(I_(AC)/I_(BC))of tetrazine-functionalized fluorogenic probes,the influence of molecular aggregation on the emission properties has been largely overlooked in these probe designs.In this study,we reveal that an ultrahigh I_(AC)/I_(BC)can be realized in the aggregate system when tetrazine is paired with aggregation-induced emission(AIE)luminogens.Tetrazine amplifies its quenching efficiency upon aggregation and drastically reduce background emissions.Subsequent click reactions damage tetrazine and trigger significant AIE,leading to considerably enhanced I_(AC)/I_(BC).We further showcase the capability of these ultra-fluorogenic systems in selective imaging of multiple organelles in living cells.We term this unique fluorogenicity of AIE luminogen-quencher complexes with amplified dark-bright states as“Matthew effect”in aggregate emission,potentially providing a universal approach to attain ultrahigh I_(AC)/I_(BC)in diverse fluorogenic systems.

A Simple Approach to Bioconjugation at Diverse Levels: Metal-Free Click Reactions of Activated Alkynes with Native Groups of Biotargets without Prefunctionalization

Te efcient bioconjugation of functional groups/molecules to targeted matrix and bio-related species drives the great development of material science and biomedicine,while the dilemma of metal catalysis,uneasy premodifcation,and limited reaction efciency in traditional bioconjugation has restricted the booming development to some extent.Here,we provide a strategy for metal-free click bioconjugation at diverse levels based on activated alkynes.As a proof-of-concept,the abundant native groups including amine,thiol,and hydroxyl groups can directly react with activated alkynes without any modifcation in the absence of metal catalysis.Trough this strategy,high-efcient modifcation and potential functionalization can be achieved for natural polysaccharide,biocompatible polyethylene glycol(PEG),synthetic polymers,cell penetrating peptide,protein,fast whole-cell mapping,and even quick diferentiation and staining of Gram-positive bacteria,etc.Terefore,current metal-free click bioconjugation strategy based on activated alkynes is promising for the development of quick fuorescence labeling and functional modifcation of many targets and can be widely applied towards the fabrication of complex biomaterials and future in vivo labeling and detection.

Strategies in boosting photosensitization for biomedical applications

Photodynamic therapy(PDT)has emerged as an effective treatment method for its few adverse effects,little invasiveness,short treatment time and low cost[1,2].The rapid development of PDT has dramatically boosted its multifaceted applications in cancer treatment,antibacterial and immunotherapy,etc.[3-5].

Taming Reactive Oxygen Species:Mitochondria-Targeting Aggregation-Induced Emission Luminogen for Neuron Protection via Photosensitization-Triggered Autophagy

Oxidative damage to cells leads to accumulated harmful wastes,which in turn aggravate the imbalance of reactive oxygen species(ROS)and related diseases.Therefore,provoking the cellular defense system against severe oxidation and maintaining ROS homeostasis are desired.Herein,we designed and synthesized a powerful mitochondria-targeting aggregation-induced emission photosensitizer(named DTCSPY)by maximal restriction of heat dissipation.It is demonstrated that taming ROS generation within mitochondria through photosensitization-triggered autophagy via DTCSPY achieved a better neuroprotective effect against oxidative damages than Nacety-L-cysteine and vitamin C.This work not only provides a new way to design high-performance photosensitizers by regulating the photophysical property,but also verifies the concept that taming ROS can be used for cell protection against destructive oxidation,thereby displaying broad prospects for alleviating oxidation-related diseases and promoting cell-based therapy.

Aptamer-Anchored Rubrene-Loaded Organic Nanoprobes for Cancer Cell Targeting and Imaging

Fluorescence imaging has become an indispensable technique in cancer research because it can reveal informative molecular,cellular,anatomical,and func-tional insights.Development of advanced fluores-cent probes with superior sensitivity and biological selectivity for fluorescence imaging is thus impera-tive.To move forward in this direction,we developed an easy self-assembly method for fabricating apta-mer-anchored rubrene-loaded organic fluorescent nanoprobes.The aptamer-modified organic nanop-robes integrated the best features of the organic light-emitting materials and the aptamers,thus endowing them with excellent cell-targeting capabil-ity,high stability,and good biocompatibility.By using this general method,a variety of biocompatible and highly bright organic fluorescent nanoprobes based on novel organic light-emitting materials with specific recognition could be easily constructed for real-time biosensing and long-term biomedical imaging.

Enzyme-free photothermally amplified fluorescent immunosorbent assay(PAFISA)for sensitive cytokine quantification

Cytokine monitoring has attracted great attention due to its significance in the diagnosis and treatment of many diseases,such as tumors,microbial infections,and immunological diseases.Enzyme-linked immunosorbent assay(ELISA)is one of the most popular methods in cytokine detection,ascribing to the lavish signal amplification methods in the ELISA platform.In addition to classical enzymes,other signal amplifiers such as fluorescent probes,artificial nano-enzymes,and photothermal reagents have been applied to reduce the detection limit and produce more sensitive ELISA kits.Due to the accumulative effect of heat,photothermal reagents are promising materials in the signal amplification of ELISA.However,the lack of efficient photothermal generation material at an aggregate scale may delay the further development of this area.In this contribution,based on an efficient organic photothermal aggregate material,an enzyme-free photothermally amplified fluorescent immunosorbent assay system consisting of an assay microfluidic chip and detecting platform was developed.The photothermal nanoparticles with highly efficient photothermal conversion by harvesting energy via excited-state intramolecular motions and enlarging molar absorptivity were successfully prepared.The detection concentration at 50 pg/mL of interleukin-2 was achieved,realizing a signal improvement of detection limits by 20-fold compared to that of previously reported photothermal ELISA.The microscopic imaging integrated with plane sweeping technology provided high spatial resolution and precision,indicating the potential of achieving high throughput profiling at the microscale.Moreover,as an alternative excitation source,light-emitting diode not only provided a more affordable and miniaturized detection system but also revealed the great feasibility of intramolecular motion-induced photothermy nanoparticles for biological analyses.

A versatile AIE fluorogen with selective reactivity to primary amines for monitoring amination,protein labeling,and mitochondrial staining

Specific bioconjugation for native primary amines is highly valuable for both chemistry and biomedical research.Despite all the efforts,scientists lack a proper strategy to achieve high selectivity for primary amines,not to mention the requirement of fast response in real applications.Herein,we report a chromone-based aggregation-induced emission(AIE)fluorogen called CMVMN as a self-reporting bioconjugation reagent for selective primary amine identification,and its applications for monitoring bioprocesses of amination and protein labeling.CMVMN is AIE-active and capable of solid-state sensing.Thus,its electrospun films are manufactured for visualization of amine diffusion and leakage process.CMVMN also shows good biocompatibility and potential mitochondria-staining ability,which provides new insight for organelle-staining probe design.Combined with its facile synthesis and good reversibility,CMVMN would not only show wide potential applications in biology,but also offer new possibilities for molecular engineering.