Manipulation of Nonradiative Process Based on the Aggregation Microenvironment to Customize Excited-State Energy Conversion.

ConspectusNonradiative processes with the determined role in excited-state energy conversion, such as internal conversion (IC), vibrational relaxation (VR), intersystem crossing (ISC), and energy or electron transfer (ET or eT), have exerted a crucial effect on biological functions in nature. Inspired by these, nonradiative process manipulation has been extensively utilized to develop organic functional materials in the fields of energy and biomedicine. Therefore, comprehensive knowledge and effective manipulation of sophisticated nonradiative processes for achieving high-efficiency excited-state energy conversion are quintessential. So far, many strategies focused on molecular engineering have demonstrated tremendous potential in manipulating nonradiative processes to tailor excited-state energy conversion. Besides, molecular aggregation considerably affects nonradiative processes due to their ultrasensitivity, thus providing us with another essential approach to manipulating nonradiative processes, such as the famous aggregation-induced emission. However, the weak interactions established upon aggregation, namely, the aggregation microenvironment (AME), possess hierarchical, dynamic, and systemic characteristics and are extremely complicated to elucidate. Revealing the relationship between the AME and nonradiative process and employing it to customize excited-state energy conversion would greatly promote advanced materials in energy utilization, biomedicine, etc., but remain a huge challenge. Our group has devoted much effort to achieving this goal.In this Account, we focus on our recent developments in nonradiative process manipulation based on AME. First, we provide insight into the effect of the AME on nonradiative process in terms of its steric effect and electronic regulation, illustrating the possibility of nonradiative process manipulation through AME modulation. Second, the distinct enhanced steric effect is established by crystallization and heterogeneous polymerization to conduct crystallization-induced reversal from dark to bright excited states and dynamic hardening-triggered nonradiative process suppression for highly efficient luminescence. Meanwhile, promoting the ISC process and stabilizing the triplet state are also manipulated by the crystal and polymer matrix to induce room-temperature phosphorescence. Furthermore, the strategies employed to exploit nonradiative processes for photothermy and photosensitization are reviewed. For photothermal conversion, besides the weakened steric effect with promoted molecular motions, a new strategy involving the introduction of diradicals upon aggregation to narrow the energy band gap and enhance intermolecular interactions is put forward to facilitate IC and VR for high-efficiency photothermal conversion. For photosensitization, both the enhanced steric effect from the rigid matrix and the effective electronic regulation from the electron-rich microenvironment are demonstrated to facilitate ISC, ET, and eT for superior photosensitization. Finally, we explore the existing challenges and future directions of nonradiative process manipulation by AME modulation for customized excited-state energy conversion. We hope that this Account will be of wide interest to readers from different disciplines.

Photodynamic Therapy Derived Personalized Whole Cell Tumor Vaccine Prevents Postsurgery Tumor Recurrence and Metastasis.

In order to avoid the time-consuming and laborious identification of tumor-specific antigens (TSAs) during the traditional vaccine fabrication process, a versatile photodynamic therapy (PDT)-based method is developed to construct a whole-tumor antigen tumor vaccine (TV) from surgically resected tumor tissues for personalized immunotherapy. Mucoadhesive nanoparticles containing small-molecular photosensitizer are fabricated and directly co-incubated with suspended tumor cells obtained after cytoreduction surgery. After irradiation with a 405 nm laser, potent immunogenic cell death of cancer cells could be induced. Along with the release of TSAs, the as-prepared TV could activate safe and robust tumor-specific immune responses, leading to efficient suppression of postsurgery tumor recurrence and metastasis. The as-prepared TV cannot only be applied alone through various administration routes but also synergize with immunoadjuvant, chemotherapeutics, and immune checkpoint blockers to exert more potent immune responses. This work provides an alternative way to promote the clinical translation of PDT, which is generally restricted by the limited penetration of light. Moreover, the versatile strategy of vaccine fabrication also facilitates the clinical application of personalized whole-cell tumor vaccines.

Metal-Free Catalytic Formation of a Donor-Acceptor-Donor Molecule and Its Lewis Acid-Adduct Singlet Diradical with High-Efficient NIR-II Photothermal Conversion.

We have synthesized a quinone-incorporated bistriarylamine donor-acceptor-donor (D-A-D) semiconductor 1 by B(C6F5)3 (BCF) catalyzed C-H/C-H cross coupling via radical ion pair intermediates. Coordination of Lewis acids BCF and Al(ORF)3 (RF=C(CF3)3) to the semiconductor 1 afforded diradical zwitterions 2 and 3 by integer electron transfer. Upon binding to Lewis acids, the LUMO energy of 1 is significantly lowered and the band gap of the semiconductor is significantly narrowed from 1.93 eV (1) to 1.01 eV (2) and 1.06 eV (3). 2 and 3 are rare near-infrared (NIR) diradical dyes with broad absorption both centered around 1500 nm. By introducing a photo BCF generator, 2 can be generated by light-dependent control. Furthermore, the integer electron transfer process can also be reversibly regulated via the addition of CH3CN. In addition, the temperature of 2 sharply increased and reached as high as 110 °C in 10 s upon the irradiation of near-infrared-II (NIR-II) laser (1064 nm, 0.7 W cm-2), exhibiting a fast response to laser. It displays excellent photothermal stability with a photothermal (PT) conversion efficiency of 62.26 % and high-quality PT imaging.

77 % Photothermal Conversion in Blatter-Type Diradicals: Photophysics and Photodynamic Applications.

Diradicals based on the Blatter units and connected by acetylene and alkene spacers have been prepared. All the molecules show sizably large diradical character and low energy singlet-triplet gaps. Their photo-physical properties concerning their lowest energy excited state have been studied in detail by steady-state and time-resolved absorption spectroscopy. We have fully identified the main optical absorption band and full absence of emission from the lowest energy excited state. A computational study has been also carried out that has helped to identify the presence of a conical intersection between the lowest energy excited state and the ground state which produces a highly efficient light-to-heat conversion of the absorbed radiation. Furthermore, an outstanding photo-thermal conversion 77.23 % has been confirmed, close to the highest in the diradicaloid field. For the first time, stable diradicals are applied to photo-thermal therapy of tumor cells with good stability and satisfactory performance at near-infrared region.

Janus-Structural AIE Nanofiber with White Light Emission and Stimuli-Response.

White-light emitting elastomers (WLEEs) based on stimuli-responsive aggregation-induced emission (AIE) and regulated Förster resonance energy transfer (FRET) have aroused increasing attention due to the demands for wearable optoelectronic devices. Herein, the blue and orange AIEgens with different environmental sensitivities are synthesized and then encapsulated on both sides of nanofibers via side-by-side electrospinning aiming to achieve the Janus WLEEs. After regulating the blue-orange AIEgens ratio, efficient and stable white light emission with a CIE coordinate of about (0.33, 0.31) is achieved at a blue-orange AIEgens mass ratio of 3:1. Besides, the Janus nanofibers (Janus-NFs) also present super stretchability with elongation at the break over 150% and tensile strength close to 7 MPa. The sensitivity of fluorescence for Janus-NFs to its stretching deformation is used to visualize the evolution of the microstructure of nanofibers during stretching. Moreover, the Janus-NFs are also sensitive to HCl and NH3 , of which the fluorescence color would change under HCl and NH3 fuming above 2 and 57 ppm in air, respectively. The promising applications of the white light Janus-NFs in smart fabrics, warning sensors, and anti-counterfeiting packaging are demonstrated. This finding provides an efficient strategy for achieving wearable WLEEs with multiple functionalities, promoting the development of wearable devices.

Emission-Tunable Soft Porous Organic Crystal Based on Squaraine for Single-Crystal Analysis of Guest-Induced Gate-Opening Transformation.

Soft porous crystals (SPCs) with both crystallinity and flexibility have evolved as emerging materials for lots of applications. However, the development of purely organic SPCs (SPOCs) with advanced functionalities significantly lags behind. Herein, we report the construction of an emission-tunable SPOC with a rationally designed squaraine derivative (named as SPOC-SQ). SPOC-SQ is featured with a squaraine core and four peripheries with electron donor-π-acceptor (D-π-A) characteristics, which facilitates the formation of porous crystal framework stabilized by π-π interactions and H bonds and at the same time provides structural flexibility through phenyl rotations. This SPOC can be easily obtained from its dichloromethane (DCM) solution and exhibits reversible stimuli-responsive single-crystal-to-single-crystal (SCSC) structural transformation, accompanied by bright and tunable emission. In addition, this activated SPOC (SPOC-SQ-a) selectively recognizes and absorbs acetylene (C2H2) over other gases without destroying the single crystallinity, enabling the single-crystal XRD analysis of the structural transformation. Close inspection of single-crystal XRD results of SPOC-SQ-C2H2 facilitates the understanding of the host-guest interactions. More interestingly, upon interacting with C2H2, a one-dimensional (1D) channel is formed in the crystal to adopt C2H2, which proves the SCSC process and provides molecular-level insights into the gate-opening process. Furthermore, C2H2 adsorption dynamics can be monitored in real time by tracking the fluorescence wavelength changes of SPOC-SQ framework. Thus, the unique gate-opening sorption attribute of SPOC-SQ-a crystals toward C2H2 enables its potential applications for gas separation.

Core-Shell Fluorescent Polymeric Particles with Tunable White Light Emission Based on Aggregation Microenvironment Manipulation.

White-light emitting polymers (WLEPs) based on aggregation microenvironment-sensitive aggregation-induced emission (AIE) and Förster resonance energy transfer (FRET) have aroused great interest in lighting and optoelectronic devices. Herein, we developed a novel strategy to construct WLEP particles via a stepwise self-stabilized precipitation polymerization of two emission-complementary AIEgens under core-shell engineering, where the AIE characteristics and FRET process of core-shell fluorescent polymeric particles (CS-FPPs) could be modulated by altering aggregation microenvironment under swelling and shrinking of polymers, facilitating the tunable white light emission of CS-FPPs. Furthermore, such tuning could be fast realized in the solid state, thus demonstrating the potential in anti-counterfeiting. This work proved the significance of aggregation microenvironment on emission of luminogens, guiding the development of high-efficiency emission-tunable materials.

Quantitative Prediction of Aggregation-Induced Emission: A Full Quantum Mechanical Approach to the Optical Spectra.

Full quantum mechanical (FQM) calculation of the excited state of aggregation-induced-emission (AIE) materials is highly sought but still a challenging task. Herein, we employed the recently developed electrostatically embedded generalized molecular fractionation (EE-GMF) method, a method based on the systematic fragmentation approach, to predict, for the first time, the spectra of a prototype AIE fluorophore: di(p-methoxylphenyl)dibenzofulvene (FTPE). Compared to the single molecular or QM/MM calculations, the EE-GMF method shows significantly improved accuracy, nearly reproducing the experimental optical spectra of FTPE in both condensed phases. Importantly, we show that the conventional restriction of the intramolecular rotation mechanism cannot fully account for AIE, whereas the two-body intermolecular quantum mechanical interaction plays a crucial role in AIE.

Fluorescence Self-Reporting Precipitation Polymerization Based on Aggregation-Induced Emission for Constructing Optical Nanoagents.

Precipitation polymerization is becoming increasingly popular in energy, environment and biomedicine. However, its proficient utilization highly relies on the mechanistic understanding of polymerization process. Now, a fluorescence self-reporting method based on aggregation-induced emission (AIE) is used to shed light on the mechanism of precipitation polymerization. The nucleation and growth processes during the copolymerization of a vinyl-modified AIEgen, styrene, and maleic anhydride can be sensitively monitored in real time. The phase-separation and dynamic hardening processes can be clearly discerned by tracking fluorescence changes. Moreover, polymeric fluorescent particles (PFPs) with uniform and tunable sizes can be obtained in a self-stabilized manner. These PFPs exhibit biolabeling and photosensitizing abilities and are used as superior optical nanoagents for photo-controllable immunotherapy, indicative of their great potential in biomedical applications.

Crystallization-Induced Reversal from Dark to Bright Excited States for Construction of Solid-Emission-Tunable Squaraines.

Squaraines (SQs) with tunable emission in the solid state is of great importance for various demands; however a remaining challenge is emission quenching upon aggregation. Herein, a unique SQ, named as CIEE-SQ, is designed to exhibit strong emission in crystal, undergoing crystallization-induced reverse from dark 1 (n+σ,π*) to bright 1 (π,π*) excited states. Such an excited state of CIEE-SQ can be subtly tuned by molecular conformation changes during the unexpected temperature-triggered single-crystal to single-crystal (SCSC) reversible transformation. Furthermore, co-crystallization between CIEE-SQ and chloroform largely stabilize the 1 (π,π*) state, enhancing the transition dipole moment and decreasing the reorganization energy to boost the fluorescence, which is promising in data encryption and decryption.

Ionization and Anion-π+ Interaction: A New Strategy for Structural Design of Aggregation-Induced Emission Luminogens.

Recent years have witnessed the significant role of anion-π+ interactions in many areas, which potentially brings the opportunity for the development of aggregation-induced emission (AIE) systems. Here, a new strategy that utilized anion-π+ interactions to block detrimental π-π stacking was first proposed to develop inherent-charged AIE systems. Two AIE-active luminogens, namely, 1,2,3,4-tetraphenyloxazolium (TPO-P) and 2,3,5-triphenyloxazolium (TriPO-PN), were successfully synthesized. Comprehensive techniques such as single-crystal analysis, theoretical calculation, and conductivity measurement were used to illustrate the effects of anion-π+ interactions on the AIE feature. Their analogues tetraphenylfuran (TPF) and 2,4,5-triphenyloxazole (TriPO-C) without anion-π+ interactions suffered from the aggregation-caused emission quenching in the aggregate state, demonstrating the important role of anion-π+ interactions in suppressing π-π stacking. TriPO-PN was biocompatible and could specifically target lysosome in fluorescence turn-on and wash-free manners. This suggested that it was a promising contrast agent for bioimaging.

A Luminescent Nitrogen-Containing Polycyclic Aromatic Hydrocarbon Synthesized by Photocyclodehydrogenation with Unprecedented Regioselectivity.

We present a nitrogen-containing polycyclic aromatic hydrocarbon (N-PAH), namely 12-methoxy-9-(4-methoxyphenyl)-5,8-diphenyl-4-(pyridin-4-yl)pyreno[1,10,9-h,i,j]isoquinoline (c-TPE-ON), which exhibits high quantum-yield emission both in solution (blue) and in the solid state (yellow). This molecule was unexpectedly obtained by a three-fold, highly regioselective photocyclodehydrogenation of a tetraphenylethylene-derived AIEgen. Based on manifold approaches involving UV/Vis, photoluminescence, and NMR spectroscopy as well as HRMS, we propose a reasonable mechanism for the formation of the disk-like N-PAH that is supported by density functional theory calculations. In contrast to most PAHs that are commonly used, our system does not suffer from entire fluorescence quenching in the solid state due to the peripheral aromatic rings preventing π-π stacking interactions, as evidenced by single-crystal X-ray analysis. Moreover, its rod-like microcrystals exhibit excellent optical waveguide properties. Hence, c-TPE-ON comprises a N-PAH with unprecedented luminescent properties and as such is a promising candidate for fabricating organic optoelectronic devices. Our design and synthetic strategy might lead to a more general approach to the preparation of solution- and solid-state luminescent PAHs.

Solid-Emission-Tunable Squaraine with Thermal-Promoted Aggregate-State Transitions for Fast Thermal History Sensing.

Determining thermal history is crucial in many industrial processes, but reliable and sensitive organic thermal history indicators are currently absent. Herein, we report on the development of a squaraine-based fluorescent molecule, DPEA-SQ, for the detection of thermal exposure histories up to 436 K. DPEA-SQ forms multiple single crystals (DPEA-SQ-I, DPEA-SQ-II, and DPEA-SQ-III) with different conformations and aggregate-state packing modes, contributing to their different fluorescence wavelengths, lifetimes, and efficiencies. Interestingly, DPEA-SQ-I and DPEA-SQ-III undergo aggregate-state structural transitions to form the thermodynamically more stable DPEA-SQ-II, which are accompanied by changes in their fluorescence. By taking advantage of similar aggregate-state structural transformations during heating, a high-temperature thermal exposure history of up to 436 K is recorded and reflected by their fluorescence. To demonstrate the potential practical applications of DPEA-SQ, a DPEA-SQ-Powder/PDMS film is prepared and coated on an electric circuit board, which enables real-time monitoring of localized overheating by the naked eye. Additionally, the fluorescence peaks of DPEA-SQ-Powder and DPEA-SQ-Powder/PDMS films remain unchanged after storage at 373 K for 52 days, demonstrating high aggregate-state stability. The fast and reliable responses of this system make it an excellent candidate for the detection of overtemperature traces in electronic components and circuit diagnosis.

Advanced Soft Porous Organic Crystal with Multiple Gas-Induced Single-Crystal-to-Single-Crystal Transformations for Highly Selective Separation of Propylene and Propane.

Soft porous organic crystals with stimuli-responsive single-crystal-to-single-crystal (SCSC) transformations are important tools for unraveling their structural transformations at the molecular level, which is of crucial importance for the rapid development of stimuli-responsive systems. Carefully balancing the crystallinity and flexibility of materials is the prerequisite to construct advanced organic crystals with SCSC, which remains challenging. Herein, a squaraine-based soft porous organic crystal (SPOC-SQ) with multiple gas-induced SCSC transformations and temperature-regulated gate-opening adsorption of various C1-C3 hydrocarbons is reported. SPOC-SQ is featured with both crystallinity and flexibility, which enable pertaining the single crystallinity of the purely organic framework during accommodating gas molecules and directly unveiling gas-framework interplays by SCXRD technique. Thanks to the excellent softness of SPOC-SQ crystals, multiple metastable single crystals are obtained after gas removals, which demonstrates a molecular-scale shape-memory effect. Benefiting from the single crystallinity, the molecule-level structural evolutions of the SPOC-SQ crystal framework during gas departure are uncovered. With the unique temperature-dependent gate-opening structural transformations, SPOC-SQ exhibits distinctly different absorption behaviors towards C3 H6 and C3 H8 , and highly efficient and selective separation of C3 H6 /C3 H8 (v/v, 50/50) is achieved at 273 K. Such advanced soft porous organic crystals are of both theoretical values and practical implications.

A new fluorometric turn-on assay for alkaline phosphatase and inhibitor screening based on aggregation and deaggregation of tetraphenylethylene molecules.

Based on the consideration that compound 1 with a -PO3H2 group can be hydrolyzed into compound 3 which shows low solubility in aqueous solutions and thus aggregation can occur easily, a new fluorescence turn-on assay has been constructed for alkaline phosphatase (ALP) with compound 1. ALP at concentrations as low as 18 mU mL(-1) can be assayed with compound 1. Moreover, compound 1 has been successfully applied for ALP assay in living cells. Also, compound 1 is useful for screening inhibitors of ALP.

Molecular and Aggregate Synergistic Engineering of Aggregation-Induced Emission Luminogens to Manipulate Optical/Electronic Properties for Efficient and Diversified Functions.

The optical/electronic properties of organic luminescent materials can be regulated by molecular structure modification, which not only requires sophisticated and time-consuming synthesis but also is unable to accurately afford the optical properties of materials in the aggregate state. Herein, a facile strategy of molecular and aggregate synergistic engineering is proposed to manipulate the optical/electronic properties of a luminogen, ACIK, in the solid state for efficient and diversified functions. ACIK is facilely synthesized and exhibits three polymorphic states (ACIK-Y, ACIK-R, and ACIK-N) with a large emission difference of 102 nm from yellow to near-infrared (NIR). Their structure-property relationships were investigated by crystallographic analyses and computational studies. ACIK-Y, with the most twisted structure, exhibits an intriguing color-tuned fluorescence between yellow and NIR in the solid state in response to multiple stimuli. Shuttle-like ACIK-R microcrystals exhibit an optical waveguide property with a low optical loss coefficient of 19 dB mm-1. ACIK dots display bright NIR-I emission, large Stokes shift, and strong NIR-II two-photon absorption. ACIK dots show specific lipid droplets-targeting capability and can be successfully applied for two-photon fluorescence imaging of mouse brain vasculature with deep penetration and high spatial resolution. This study will inspire more insights in developing advanced optical/electronic materials based on a single chromophore for practical applications.

A new ratiometric fluorescence detection of heparin based on the combination of the aggregation-induced fluorescence quenching and enhancement phenomena.

A new ratiometric fluorescence detection of heparin is reported with the ensemble of 1 and 2. This method is based on the respective ACQ (aggregation-caused quenched emission) and AIE (aggregation-induced emission) features of anthracene and tetraphenylethene. DLS, CLSM and fluorescent spectral investigations suggest that the variation of the fluorescence intensity ratio I(497)/I(421) is due to the formation of aggregates of 1 and 2 with heparin. Moreover, this ratiometric fluorescence method can be used to distinguish heparin from its analogues (HA, Dex). In order to demonstrate the practical utilization of this ratiometric fluorescence method, the fluorescence spectra of the ensemble of 1 and 2 were measured in the presence of serum, and the results indicate that it is possible to eliminate the interferences from other biomolecules by either subtracting the background fluorescence intensities or lowering the pH values of the sample solutions.

AIE-Active Photosensitizers: Manipulation of Reactive Oxygen Species Generation and Applications in Photodynamic Therapy.

Photodynamic therapy (PDT) is a non-invasive approach for tumor elimination that is attracting more and more attention due to the advantages of minimal side effects and high precision. In typical PDT, reactive oxygen species (ROS) generated from photosensitizers play the pivotal role, determining the efficiency of PDT. However, applications of traditional PDT were usually limited by the aggregation-caused quenching (ACQ) effect of the photosensitizers employed. Fortunately, photosensitizers with aggregation-induced emission (AIE-active photosensitizers) have been developed with biocompatibility, effective ROS generation, and superior absorption, bringing about great interest for applications in oncotherapy. In this review, we review the development of AIE-active photosensitizers and describe molecule and aggregation strategies for manipulating photosensitization. For the molecule strategy, we describe the approaches utilized for tuning ROS generation by attaching heavy atoms, constructing a donor-acceptor effect, introducing ionization, and modifying with activatable moieties. The aggregation strategy to boost ROS generation is reviewed for the first time, including consideration of the aggregation of photosensitizers, polymerization, and aggregation microenvironment manipulation. Moreover, based on AIE-active photosensitizers, the cutting-edge applications of PDT with NIR irradiated therapy, activatable therapy, hypoxic therapy, and synergistic treatment are also outlined.

Diradical-Featured Organic Small-Molecule Photothermal Material with High-Spin State in Dimers for Ultra-Broadband Solar Energy Harvesting.

Organic materials with radical characteristics are gaining increasing attention, due to their potential implications in highly efficient utilization of solar energy. Manipulating intermolecular interactions is crucial for tuning radical properties, as well as regulating their absorption bands, and thus improving the photothermal conversion efficiency. Herein, a diradical-featured organic small-molecule croconium derivative, CR-DPA-T, is reported for highly efficient utilization of solar energy. Upon aggregation, CR-DPA-T exists in dimer form, stabilized by the strong intermolecular π-π interactions, and exhibits a rarely reported high-spin state. Benefiting from the synergic effects of radical characteristics and strong intermolecular π-π interactions, CR-DPA-T powder absorbs broadly from 300 to 2000 nm. In-depth investigations with transient absorption analysis reveal that the strong intermolecular π-π interactions can promote nonradiative relaxation by accelerating internal conversion and facilitating intermolecular charge transfer (ICT) between dimeric molecules to open up faster internal conversion pathways. Remarkably, CR-DPA-T powder demonstrates a high photothermal efficiency of 79.5% under 808 nm laser irradiation. By employing CR-DPA-T as a solar harvester, a CR-DPA-T-loaded flexible self-healing poly(dimethylsiloxane) (H-PDMS) film, named as H-PDMS/CR-DPA-T self-healing film, is fabricated and employed for solar-thermal applications. These findings provide a feasible guideline for developing highly efficient diradical-featured organic photothermal materials.

Cascade-responsive nano-assembly for efficient photothermal-chemo synergistic inhibition of tumor metastasis by targeting cancer stem cells.

Metastasis has been widely recognized as the most lethal threats for cancer patients. Due to their special genetic and environmental context, cancer stem cells (CSCs) which are resistant to most cytotoxic drugs and radiation, are considered as the dominant culprit for metastasis. Thus, the efficient targeting and thorough elimination of CSCs are significantly urgent for the enhancement of therapeutic efficacy. Herein, we developed a facile and smart photothermal-chemo therapeutic nano-assembly system, of which the surface was modified by a sheddable PEG shell and acid-activatable pro-penetration peptide, to surmount the physiological barriers in targeting CSCs. A highly-efficient diradical-featured croconium-based photothermal agent and a natural cytotoxic heat shock protein (HSP) inhibitor were co-loaded in redox-sensitive chitosan matrices to realize the synergistic photothermal-chemo therapy. Within solid tumors, the PEG shell that prevents the nano-assembly from mononuclear phagocytic clearance could rapidly leave to expose the positively charged chitosan, and the detached iRGD could further actuate the tumor penetration of chitosan nanoparticles, and allow the CSCs targeting by selective recognition of CD44 protein. Owing to the HSP inhibition and chemo-sensitization, both the CSCs and non-CSCs could be thoroughly eliminated by the designed nano-assembly, largely inhibiting the tumor growth and metastasis. This work provides a potential strategy for CSCs-targeting drug delivery to solve the CSCs-related metastasis.