Screening of Zwitterionic Liposomes with Red Blood Cell-Hitchhiking and Tumor Cell-Active Transporting Capability for Efficient Tumor Entrance

The active transport of nanoparticles into the solid tumor through cell transcytosis has shown great promise in cancer nanomedicine, but it is challenging to develop efficient active transporting nanomedicines with the potential for clinical translation. Here, a type of tertiary amine oxide (TAO)-containing zwitterionic liposomal nanocarriers is developed that can hitchhike red blood cells (RBCs) to tumor blood vessels and enter solid tumors through transcytosis. To boost the active-transporting capability, a library of the TAO liposomes (TAOLs) with different chemical structures and particle sizes is constructed and screened by their stability and active transporting capability. Two types of TAOLs are identified that can induce efficient tumor cell transcytosis through rapid macropinocytosis and endoplasmic reticulum/Golgi-involved exocytosis. It is found that these zwitterionic TAOLs can hitchhike RBCs to gain long blood circulation, get off the cell at the tumor site, effectively enter the tumor through transcytosis, and infiltrate the whole tumor. The chemotherapeutic drug-loaded liposomes can stop the tumor progression of mice bearing human hepatocellular carcinoma HepG2 cells, exhibiting superior antitumor activity compared to the traditional liposomal drug. This study demonstrates a strategy to construct effective active transporting liposomal nanomedicines for efficient tumor entrance.     

Programmed Multiresponsive Vesicles for Enhanced Tumor Penetration and Combination Therapy of Triple‐Negative Breast Cancer

Nanomedicine is a promising approach for combination chemotherapy of triple‐negative breast cancer (TNBC). However, the therapeutic efficacy of nanoparticulate drugs is suppressed by a series of biological barriers. The authors herein present a programmed stimuli‐responsive liposomal vesicle to overcome the sequential barriers for enhanced TNBC therapy. The intelligent vesicles are engineered by integrating an enzyme‐cleavable polyethylene glycol (PEG) corona, a light‐responsive photosensitizer pheophorbide a (PPa), and a temperature‐sensitive liposome (TSL) into a single nanoplatform. The resultant enzyme, light, and temperature multisensitive liposome (ELTSL) is sequentially coloaded with a lipophilic oxaliplatin prodrug of hexadecyl‐oxaliplatin carboxylic acid (HOC) and hydrophilic doxorubicin hydrochloride (DOX). Dual drug‐loaded ELTSL displays enhanced tumor penetration and increased cellular uptake upon matrix metalloproteinase 2 mediated cleavage of the PEG corona. Under NIR laser irradiation, PPa induces mild hyperthermia effect to trigger ultrafast drug release in the tumor cells. In combination with PPa‐mediated photodynamic therapy, HOC and DOX coloaded ELTSL show significantly improved antitumor efficacy than monotherapy. Given the clinically translatable potential of the liposomal vesicles, ELTSL might represent a promising nanoplatform for combination TNBC therapy.     

Tumor Microenvironment Responsive Drug‐Dye‐Peptide Nanoassembly for Enhanced Tumor‐Targeting,Penetration, and Photo‐Chemo‐Immunotherapy

Nanomedicine constructed by therapeutics has unique and irreplaceable advantages in biomedical applications, especially in drug delivery for cancer therapy. The strategy, however, used to construct the therapeutics‐based nanomedicines with tumor microenvironmental factor responsiveness is still sophisticated. In this study, an easy‐operating procedure is used to construct a therapeutics‐based nanosystem with active tumor‐targeting, enhanced penetration, and stimuli‐responsive drug release behavior as well as programmed cell death‐1/programmed cell death‐ligand 1 (PD‐1/PD‐L1) blockading mediated immunomodulation to enhance tumor immunotherapy. The matrix metalloproteinase‐2 responsive peptide with the existence of Lyp‐1 sequence contributes to the success of active tumor‐targeting and the enhancement of the penetration of the nanoparticles in tumor tissue. The obtained nanosystem strikingly inhibits the primary tumor growth in the first 24 h (more than 97.5% of tumor cells are inhibited), and total inhibition can be achieved with the combination of photothermal therapy. IR820, which is served as the carrier for the therapeutics, is used as a photosensitizer for photothermal therapy. The progress and aggression of distal tumor has further been alleviated by a d ‐peptide which is an antagonist for PD‐1/PD‐L1 blockage. Therefore, a therapeutics‐constructed multifunctional nanosystem is provided to realize a combinational therapeutic strategy to enhance the therapeutic outcome.     

Bacteria‐Assisted Selective Photothermal Therapy for Precise Tumor Inhibition

Photothermal therapy (PTT) has drawn extensive research attention as a promising approach for tumor treatment. In this study, a bacteria‐assisted strategy relying on the selective reduction of perylene diimide derivative based supramolecular complex (CPPDI) to radical anions (RAs) by Escherichia coli in hypoxic tumors is developed to realize highly precise PTT of tumors. Noninvasive E. coli are first injected intravenously for selectively accumulating and replicating in the tumor due to the hypoxia tropism. Then, CPPDI is loaded in a peptide‐hybrid matrix metalloproteinase‐2 (MMP‐2) responsive liposome (MRL) and injected intravenously. After accumulated and released from MRL in the tumor where MMP‐2 is overexpressed, CPPDI is reduced by E. coli in the hypoxic tumor environment to produce CPPDI RAs (CRAs), which serve as effective photothermal agents for tumor cells thermal ablation under near‐infrared light irradiation. Since E. coli accumulate and grow in tumor sites selectively, this strategy accurately limits the production of CRAs in tumors for highly selective PTT, which will find great potential for precise tumor inhibition.     

An ultrasonically powered implantable micro-oxygen generator (IMOG)

In this paper, we present an ultrasonically powered implantable micro-oxygen generator (IMOG) that is capable of in situ tumor oxygenation through water electrolysis. Such active mode of oxygen generation is not affected by increased interstitial pressure or abnormal blood vessels that typically limit the systemic delivery of oxygen to hypoxic regions of solid tumors. Wireless ultrasonic powering (2.15?MHz) was employed to increase the penetration depth and eliminate the directional sensitivity associated with magnetic methods. In addition, ultrasonic powering allowed for further reduction in the total size of the implant by eliminating the need for a large area inductor. IMOG has an overall dimension of 1.2 mm × 1.3 mm × 8?mm, small enough to be implanted using a hypodermic needle or a trocar. In vitro and ex vivo experiments showed that IMOG is capable of generating more than 150?μA which, in turn, can create 0.525?μL/min of oxygen through electrolytic disassociation. In vivo experiments in a well-known hypoxic pancreatic tumor models (1 cm (3) in size) also verified adequate in situ tumor oxygenation in less than 10 min.     

Sequentially Targeting Cancer-Associated Fibroblast and Mitochondria Alleviates Tumor Hypoxia and Inhibits Cancer Metastasis by Preventing “Soil” Formation and “Seed” Dissemination

Tumor metastasis is facilitated by the formation of the premetastatic niche (PMN) in destination organs and the dissemination of cancer cells detached from a primary tumor. This study reports a sequential combination strategy that exerts a profound anti-metastasis effect by inhibiting both PMN formation and cancer cell dissemination. The approach consists of (1) cancer-associated fibroblast cells (CAFs)-targeting liposome and (2) mitochondria-targeting polymer. The liposome depletes CAFs and reduces tumor stroma, leading to a significant increase in intratumoral oxygen perfusion. The polymer disrupts mitochondria aerobic respiration in cancer cells, leading to a considerable decrease in intratumoral oxygen consumption. With the complementary mechanisms, their combination drastically alleviates the hypoxia in orthotopic breast tumor and inhibits the pulmonary PMN formation by downregulating various hypoxia-induced PMN-fostering factors. In addition, the CAFs depletion by the liposome abrogates the metastasis-promoting crosstalk with cancer cells; meanwhile, mitochondria dysfunction by the polymer cuts off the energy supply that supports metastasis, together resulting in an efficient suppression of cancer cell dissemination. With the two-pronged strategy targeting these two aspects, the primary tumor is prominently inhibited, and distant metastasis is completely eradicated. This study provides a generalizable approach of sequential CAFs depletion and mitochondria disruption to combat metastatic tumors.     

Size/Charge Changeable Acidity‐Responsive Micelleplex for Photodynamic‐Improved PD‐L1 Immunotherapy with Enhanced Tumor Penetration

The checkpoint blockade‐based immunotherapy has recently emerged as a promising approach for tumor treatment, but its clinical implementation has been impeded by poor tumor penetration of the nanocarriers and activation of antitumor immune response. To overcome the obstacles, a tumor acidity‐responsive micellar nanocomplex co‐loaded with programmed death‐ligand 1 (PD‐L1)‐blockade siRNA and mitochondrion‐targeting photosensitizer for the synergistic integration of photodynamic therapy and immunotherapy is reported in the present study. The nanosystem is coated with long‐circulating polyethylene glycol (PEG) shells, which can be shed in response to the weakly acidic tumor microenvironment and lead to significant size reduction and increasing positive charge. These transitions facilitate penetration and uptake of nanocarriers against tumors. Subsequently, under the mild acidic endo/lysosome condition, the micellar nanocomplexes are rapidly protonated and disintegrated to release the PD‐L1‐blockade siRNA and photosensitizer through sponge effect. Results from in vitro and in vivo experiments collectively reveal that the nanosystem efficiently activates a photodynamic therapy‐induced immune response and silences immune resistance mediated by the checkpoint gene PD‐L1. In consequence, melanoma growth is inhibited and the recurrence rate is reduced via triggering systemic antitumor immune responses. This study offers an alternative strategy for the development of efficient antitumor immune therapy.     

Hierarchically Responsive Tumor-Microenvironment-Activated Nano-Artificial Virus for Precise Exogenous and Endogenous Apoptosis Coactivation

Targeting apoptotic pathways in tumor cells is recognized as a potent anticancer strategy. However, monotherapies that target a single apoptotic pathway often do not meet expectations and the nonspecific and uncontrolled activation of apoptotic pathways can overshadow potential application prospects. Here, a novel tumor-microenvironment-activated nano-artificial virus (TMAN) with hierarchically responsive capacity is fabricated and loaded with the plasmid encoding tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and mitochondria-targeted red fluorescent phototoxic protein (KillerRed) simultaneously for precise and controllable exogenous and endogenous apoptosis coactivation. The inert TMAN is endowed with in vivo longevity and undergoes orderly acidity-triggered deshielding of a masking layer, enzyme-responsive charge-reversal, and oxidative stress-sensitive structural fragmentation in the tumor extra/intracellular microenvironment to exert precise tumor recognition, deep penetration, cellular internalization, rapid endosomes escape, and effective gene release ability, leading to the effective and tumor-specific delivery of payloads. Given the virtues of TMAN, a favorable collaboration of TRAIL-triggered exogenous apoptosis and mitochondria-targeted KillerRed induced endogenous apoptosis is achieved synchronously under the control of light irradiation, thus remarkably improving antitumor efficacy with minimal toxicity. Taken together, this strategy highlights the significance of exogenous and endogenous apoptosis coactivation in cancer treatments and offers a promising paradigm for precise exo/endogenous dual-augmented antitumor therapy.     

Rational Design of Nanoparticles with Deep Tumor Penetration for Effective Treatment of Tumor Metastasis

The limited penetration of nanoparticles in primary tumors and metastases remains a great challenge for effective treatment of tumor metastasis. This review outlines the current approaches and summarizes the rational design of nanoparticles with deep tumor penetration capacity for anti‐metastasis treatment. There are two ways to achieve better tumor penetration; through rational regulation of the physicochemical properties of nanoparticles and through remodeling of the tumor microenvironment, including the tumor vasculature and stromal environment. Moreover, biomimetic strategies that integrate the advantages of nanoparticles and metastasis‐homing molecules during cancer cell metastasis are discussed. These efforts have led to promising results in facilitating intratumoral permeation of various nanoparticles to enhance antitumor effects. The considerations and some feasible future directions for deep tumor penetration strategies are proposed to improve tumor metastasis therapies.     

Hierarchically Targeted and Penetrated Delivery of Drugs to Tumors by Size‐Changeable Graphene Quantum Dot Nanoaircrafts for Photolytic Therapy

Theranostic nanohybrids are promising for effective delivery of therapeutic drug or energy and for imaging‐guided therapy of tumors, which is demanded in personalized medicine. Here, a size‐changeable graphene quantum dot (GQD) nanoaircraft (SCNA) that serves as a hierarchical tumor‐targeting agent with high cargo payload is developed to penetrate and deliver anticancer drug into deep tumors. The nanoaircraft is composed of ultrasmall GQDs (less than 5 nm) functionalized with a pH‐sensitive polymer that demonstrates an aggregation transition at weak acidity of tumor environment but is stable at physiological pH with stealth function. A size conversion of the SCNA at the tumor site is further actuated by near‐infrared irradiation, which disassembles 150 nm of SCNA into 5 nm of doxorubicin (DOX)/GQD like a bomb‐loaded jet, facilitating the penetration into the deep tumor tissue. At the tumor, the penetrated DOX/GQD can infect neighboring cancer cells for repeated cell killing. Such a SCNA integrated with combinational therapy successfully suppresses xenograft tumors in 18 d without distal harm. The sophisticated strategy displays the hierarchically targeted and penetrated delivery of drugs and energy to deep tumor and shows potential for use in other tumor therapy.     

An Integrated Nanoaircraft Carrier Modulating Antitumor Immunity to Enhance Immune Checkpoint Blockade Therapy

Immune checkpoint blockade (ICB) therapy revolutionizes cancer therapeutics. However, the effectiveness of ICB therapy is restricted. Focusing on the tumor itself and the immune system, an integrated nanoaircraft carrier that coloaded three therapeutic agents (NNG/OTC) to eradicate tumor cells, enhance T-cells intratumoral infiltration, and relieve the inhibition of tumor immunosuppressive microenvironment (TIM) is designed. First, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is used to combine with oxaliplatin for reducing tumor burden. Second, oxaliplatin is used to elicit immunogenic cell death and combine with cytosine-phosphate-guanine (CpG) to promote dendritic cells maturation, ultimately increasing T-cells intratumoral infiltration. Third, CpG is further used to repolarize M2 type of tumor-associated macrophages, thus reversing immunosuppression of TIM. The nanoaircraft carrier can effectively arrive at the tumor site and detach small-sized nanoparticles under a high concentration of matrix metalloproteinase-2, which promotes deep tumor penetration. Under the mediation of targeting ligands, three therapeutic agents loaded in small-sized nanoparticles could be launched to their target cells. NNG/OTC modulates the antitumor immunity and exhibits excellent tumor inhibition when in combination with ICB therapy, indicating the increased response of ICB therapy. Collectively, NNG/OTC can co-deliver various drugs with different physicochemical properties and provide a promising strategy for enhancing ICB therapy.     

Development of an active targeting liposome encapsulated with high-density colloidal gold for transmission electron microscopy

Active targeting of the liposome is an attractive strategy for drug delivery and in vivo bio-imaging. We previously reported the specific accumulation of Sialyl Lewis X (SLX) liposome to inflamed tissue in arthritic model mice or tumor-bearing mice. SLX-liposome encapsulation with fluorescent substances allows for the visualization of these liposomes by the time-dependent transvascular accumulation of fluorescent signals in the histological sections. In the present study, we developed a new SLX-liposome encapsulated with colloidal gold for transmission electron microscopic observation. We herein describe the characterization of the colloidal gold-loaded SLX-liposomes and demonstrate its specific targeting to the endothelial cells of tumor blood vessels in tumor-bearing mice.     

Two-Photon Absorption Induced Cancer Immunotherapy Using Covalent Organic Frameworks

Immune checkpoint blockade therapy is revolutionizing the traditional treatment model of multiple tumor types, but remains ineffective for a large subset of patients. Photodynamic therapy (PDT) has been shown to induce cancer cell death and provoke an immune response, and may represent a potential strategy to synergize with immune checkpoint blockade therapy. However, the limited tissue penetration of exciting light for conventional PDT largely hinders its application in the clinic and its further combination with immunotherapy. Here, a serrated packing covalent organic framework (COF), COF-606, with excellent two-photon absorption (2PA) property and photostability, largely avoids aggregation-caused quenching, therefore offering high reactive oxygen species (ROS) generation efficiency; it is used as a 2PA photosensitizer for PDT in deep tumor tissue. COF-606 induced PDT is shown to be efficient in inducing immunogenic cell death, provoking an immune response and normalizing the immunosuppressive status for the first time. This makes it possible to combine 2PA induced PDT using COF with programmed cell death protein 1 immune checkpoint blockade therapy. Such combination leads to strong abscopal tumor-inhibiting efficiency and long-lasting immune memory effects, standing as a promising combinatorial therapeutic strategy for cancer treatment.     

Exosome as a Vehicle for Delivery of Membrane Protein Therapeutics,PH20, for Enhanced Tumor Penetration and Antitumor Efficacy

As biochemical and functional studies of membrane protein remain a challenge, there is growing interest in the application of nanotechnology to solve the difficulties of developing membrane protein therapeutics. Exosome, composed of lipid bilayer enclosed nanosized extracellular vesicles, is a successful platform for providing a native membrane composition. This study reports an enzymatic exosome, which harbors native PH20 hyaluronidase (Exo‐PH20), which is able to penetrate deeply into tumor foci via hyaluronan degradation, allowing tumor growth inhibition and increased T cell infiltration into the tumor. This exosome‐based strategy is developed to overcome the immunosuppressive and anticancer therapy‐resistant tumor microenvironment, which is characterized by an overly accumulated extracellular matrix. Notably, this engineered exosome with the native glycosylphosphatidylinositol‐anchored form of hyaluronidase has a higher enzymatic activity than a truncated form of the recombinant protein. In addition, the exosome‐mediated codelivery of PH20 hyaluronidase and a chemotherapeutic (doxorubicin) efficiently inhibits tumor growth. This exosome is designed to degrade hyaluronan, thereby augmenting nanoparticle penetration and drug diffusion. The results thus show that this is a promising exosome‐based platform that harbors not only a membrane‐associated enzyme with high activity but also therapeutic payloads.     

Sub-50 nm Supramolecular Nanohybrids with Active Targeting Corona for Image-Guided Solid Tumor Treatment and Metastasis Inhibition

Tumor metastasis is responsible for almost 90% of failure in cancer therapy and it is also the major cause of cancer-associated mortality due to poor vascularization. Herein, a sub-50 nm hybrid theranostic robust nanoplatform is developed via a template supramolecular strategy to achieve active targeting and deep penetration of primary tumors as well as metastatic tumors with poor vascular structures. Quantum dots (QDs) as a template are coordinated with lipoic acid (LA)-functionalized dendrimers for covalent loading of doxorubicin (DOX) and Arg-Gly-Asp (RGD) tripeptide-functionalized polyethylene glycol (PEG) for prolonging blood circulation and selectively targeting cancer cells. When the nanohybrid is internalized into tumor cells, DOX releases from the nanohybrid in acidic lysosomes and is translocated into nuclei for arresting cell cycles at the G2/M phase, leading to a remarkably therapeutic effect for both primary tumors and distant metastases in a 4T1 xenograft tumor model. The inherent fluorescence of QDs in the nanohybrid allows real-time monitoring of the therapeutic responses from primary and metastasis tumors. Hence, a facile strategy is demonstrated to construct a hybrid nanoplatform with multifunctionality for inhibition of both primary and metastatic cancer.     

Model-Based Control of Active Tilting-Pad Bearings

A promising mechanical bearing candidate for an active operation is the tilting-pad bearing. The proposed active tilting-pad bearing has linear actuators that radially translate each pad/pivot pair. The use of feedback control in determining the actuator forces allows for the automatic, continuous adjustment of the pad position during the operation of the rotating machine. In this paper, we develop a nonlinear dynamic model of the active bearing system. The hydrodynamic force produced by the fluid film is modeled as a nonlinear, squeeze-film damper plus repellent spring. A model-based nonlinear controller is then designed to exponentially regulate the rotor position to the origin. A proof-of-concept experiment shows that the active strategy improves the bearing performance relative to its traditional passive operation. Further, the experiment demonstrates that the model-based nonlinear control regulates the rotor comparably to a linear proportional integral derivative (PID) control, but requires significantly less control energy.     

Amplifying Nanoparticle Targeting Performance to Tumor via Diels–Alder Cycloaddition

Traditional targeting approach utilizing biological ligands has to face the problems of limited receptors and tumor heterogeneity. Herein, a two‐step tumor‐targeting and therapy strategy based on inverse electron‐demand [4+2] Diels–Alder cycloaddition (iEDDA) is described. Owing to the unique acidic tumor microenvironment, an intravenous injection of tetrazine modified pH (low) insertion peptide could efficiently target and incorporate onto various cell surfaces in tumor tissue, such as cancer cells, vascular endothelial cells, and tumor‐associated fibroblasts. The “receptor‐like” tetrazine groups with a large amount and homogeneous intratumoral distribution could then serve as the baits to greatly amplify the tumor‐targeting ability of indocyanine green (ICG)‐loaded and trans‐cyclooctene (TCO)‐conjugated human serum albumin (HSA) nanoparticles (TCO‐HSA‐ICG NPs) via iEDDA after the second intravenous injection. Compared with the passive enhanced permeability and retention (EPR) effect and traditional active targeting approaches, the targeting performance and photothermal therapeutic effect based on the two‐step strategy are significantly enhanced, while no notable toxicity is observed. As acidity is a characteristic of solid tumor, the two‐step strategy can serve as a universal and promising modality for safe and high‐performance nanoparticle‐based antitumor therapy.     

Fluorination-Induced Multi-Enhancement of a Nano-Photosensitizer for Deep Photodynamic Therapy against Hypoxia Tumor

Organic dyes hold great promise for application in photodynamic therapy (PDT). However, they currently face challenges such as inadequate photodynamic activity, limited tumor penetration, and constraints imposed by tumor hypoxia. Here, a facile and efficient strategy is presented for multi-enhanced PDT through the fluorination of a squarylium indocyanine dye-based photosensitizer (FCy). The amphiphilic FCy features perfluorooctane and PEG-biotin moieties conjugated to a squarylium indocyanine core. In aqueous environments, FCy spontaneously self-assembles into stable nano-sized photosensitizers (FCy NPs), demonstrating a high oxygen loading ability attributable to the presence of perfluoroalkyl groups. Consequently, the aggregation of squarylium indocyanine dyes remarkably boosts the photodynamic effect, yielding a 15-fold improvement in singlet oxygen quantum yield. Owing to the perfluoroalkyl group, FCy NPs exhibit increased endoplasmic reticulum (ER)- accumulating abilities, which further induce ER stress upon laser irradiation and enhance the PDT effect. Furthermore, the superior deep tumor penetration ability of FCy NPs is confirmed through both in vitro and in vivo studies. With efficient oxygen supply to the deep tumor regions, FCy NPs demonstrate potent imaging-guided PDT against hypoxia tumors. The study substantiates the enhanced ER-accumulating ability of the perfluoroalkyl group and presents a facile fluorination strategy for the multi-enhancement of photosensitizers.     

Active deception defense method based on dynamic camouflage network

In view of the problem that the existing honeypots often fail to resist the penetration attack due to the lack of confidentiality,an active deception defense method based on dynamic camouflage network (DCN) was presented.The definition of DCN was given firstly,and then the attacker-defender scenario of active deception based on DCN was described.Next,the interaction process of the attacker-defender scenario was modeled by using a signaling game,whose equilibrium can guide the selection of optimal deception strategy.Furthermore,to quantify the payoffs accurately,the two-layer threat penetration graph (TLTPG) was introduced.Finally,the solution for game equilibrium was designed,through which pure strategy and mixed strategy could be calculated simultaneously.The experimental results show that,based on the dynamic camouflage network,the perfect Bayesian equilibrium can provide effective guidance for the defender to implement the optimal defense strategy and maximize the benefits of the defender.In addition,the characteristics and rules of active deception defense DCN-based are summarized.     

Tumor-Activated Photosensitization and Size Transformation of Nanodrugs

Effective intratumoral distribution of anticancer agents with good tumor penetration is of practical importance for photo-chemotherapy. Herein, a metal-organic framework (MOF) assisted strategy is reported for smart delivery of aggregation-induced emission photosensitizer (AIE PS) and chemodrug for deep tumor penetration to realize effective image-guided photo-chemotherapy. A newly designed AIE PS is loaded inside an iron(III) carboxylate-based MOF, MIL-100, to produce PS@MIL-100, which is encapsulated by doxorubicin (Dox) conjugated poly(ethylene glycol) methyl ether (PEG) to yield Dox-PEG-PS@MIL nanoparticles (NPs) with a diameter of 120 nm. After Dox-PEG-PS@MIL NPs reached the tumor site, intratumoral H₂O₂ can cause the release of the loaded PS at the tumor surface for activatable photodynamic therapy (PDT). The Dox-PEG segment is simultaneously triggered to self-assemble into ultrasmall Dox NPs. Under light irradiation, PDT is activated at the tumor surface, synergistically enhancing the tumor penetration of Dox NPs along with their ultrasmall size. After endocytosis of Dox NPs, free Dox is released from Dox NPs under low pH to enter cell nuclei for effective chemotherapy. Accompanied by bright far-red/near-infrared emission from the PS, image-guided photo-chemotherapy with enhanced efficacy is achieved.