Deep Tumor Penetration Research Articles

Size Switchable Nanoclusters Fueled by Extracellular ATP for Promoting Deep Penetration and MRI‐Guided Tumor Photothermal Therapy

AbstractProtein‐based theranostic agents (PBTAs) exhibit superior performance in the diagnosis and therapy of cancers. However, the in vivo applications of PBTA are largely limited by undesired accumulation, penetration, or selectivity. Here, an ATP‐supersensitive protein cluster is fabricated for promoting PBTA delivery and enhancing magnetic resonance imaging (MRI)‐guided tumor photothermal therapy. Gd3+‐ and CuS‐coloaded small bovine serum albumin nanoparticles (GdCuB) are synthesized as the model protein with a size of 9 nm and are encapsulated into charge switchable polycations (DEP) to form DEP/GdCuB nanoclusters of 120 nm. In blood circulation, DEP/GdCuB significantly extends the half‐lifetime and thereby enhances the tumor accumulation of GdCuB. When the clusters reach the tumor site, the extracellular adenosine triphosphate (ATP) can effectively trigger the release of GdCuB, resulting in tumoral deep penetration as well as the activation of T1‐weighted MRI (r1 value switched from 2.8 × 10−3 to 11.8 × 10−3 m−1 s−1). Furthermore, this delivery strategy also improves the tumoral photothermal therapy efficacy with the MRI‐guided therapy. The study of ATP‐activated nanoclusters develops a novel strategy for tumor deep penetration and on/off imaging of PBTA by size switchable technology, and reveals the potential for MRI‐guided therapy of cancers.

Nano-engineered lymphocytes for alleviating suppressive tumor immune microenvironment

The intrinsic trafficking ability of host cells to infiltrate various disease sites and act as living chaperones for chemotherapeutics alone or chemotherapeutics-loaded nanoparticles to actively transmigrate the endothelial barrier within solid tumor and achieve efficient tumor accumulation is being explored in a quantity of contexts. Here, we leveraged tumor-infiltrating T lymphocytes as delivery vehicle to increase the tumor apoptosis and immunogenic cell death (ICD) of doxorubicin to efficiently boost immune response and eliminate the tumor growth. First we decorated the redox responsive doxorubicin-albumin conjugates (DOX-A) onto the surface of T lymphocytes (DOX-A@T cell) via a pH sensitive bond, which allows for stable retention of DOX-A on the surface of T lymphocytes in blood circulation but the responsive release of DOX-A within the weak acid tumor microenvironment. The released DOX-A exerted deep tumor penetration, efficient tumor cell uptake and rapid intracellular drug release via redox responsive cleavage. We showed that DOX-A can be stably conjugated to the surface of T lymphocytes for at least 6h without any detectable toxicity or interference with intrinsic cell functions. DOX-A@T cell had the strong tumor infiltration and penetration both in vitro and in vivo. More significantly, this DOX-A@T cell actively efficiently augmented the DOX-induced ICD efficacy through activation of dendritic cells (DCs) and consequent activation of specific T cell response, thus potentiating immune response in tumor microenvironment.

Preparation of iron oxide mesoporous magnetic microparticles as novel multidrug carriers for synergistic anticancer therapy and deep tumor penetration

The preparation of mesoporous iron oxides with controllable physiochemical properties for effective therapeutic drug delivery remains a formidable challenge. Herein, iron oxide mesoporous magnetic microparticles (IO-MMMs) were prepared by a modified reverse hard-templating approach using, for the first time, acid-prepared mesoporous spheres (APMS) as the hard silica template. The obtained mesostructures exhibited remarkably high surface area and large pore volumes (SBET = 240 m2/g and Vpore = 0.55 cm3/g), controllable average sizes, generally uniform morphologies, and excellent biocompatibilities, allowing them to achieve optimal drug release in cancer cells and tumor tissues. IO-MMM carriers were able to co-load high amounts of hydrophilic chemotherapeutic drugs (Dox or Daun) and/or hydrophobic hormonal anticancer drugs (Tam), and release them sustainably in a pH-dependent manner, utilizing the fluorescence of Daun to real-time trace the intracellular drug distribution, and employing Daun/Tam to treat cancer by combined chemo/hormonal therapy. Cytotoxicity assays against different types of cancerous cells showed that the combinatory Daun/Tam@IO-MMM formulation significantly reduced the viability of metastatic MCF7 and KAIMRC1 breast as well as HCT8 colorectal cancer cells, with the least potency towards non-cancerous normal primary cells (up to 10-fold). Electron, flow, and live confocal microscopy imaging confirmed that the loaded vehicles were successfully and differentially uptaken by the different tested cells, gradually releasing their payloads, and causing apoptotic cell death. Importantly, compared to free drugs, Daun/Tam@IO-MMMs displayed enhanced drug accumulation in patient breast primary tumor tissues, deeply penetrating into the tumor region and killing the tumor cells inside. The designed carriers described here, thus, constitute a novel promising magnetic mesoporous smart system that entraps different kinds of drugs and release them in a controlled manner for combinatorial chemo/hormonal cancer theranostics. This multifactorial platform may open new avenues in cancer therapy as efficient synergistic antitumor system through overcoming limitations of conventional cancer therapy.

Enzyme-powered Janus nanomotors launched from intratumoral depots to address drug delivery barriers

The delivery of nanoparticles encounters a series of biological barriers from systemic clearance, tumor accumulation, cellular uptake and intracellular drug release. In this study we propose enzyme-powered nanomotors launched from intratumorally injected local depots to overcome these delivery barriers. Hydroxyapatite-embedded mesoporous silica nanoparticles (Hap@MSN) are prepared by formation of silica layers on CaCO3 nanoparticles, transformation of CaCO3 into Hap cores, and camptothecin (CPT) loading. Janus nanoparticles (JPs) are obtained by the selective deposition of gold layer on one side of Hap@MSN. Janus nanomotors (JNMs) are constructed by separately grafting hyaluronic acid (HA) and urease on the opposite sides of JPs as the targeting moiety and power source, respectively. JNMs indicate self-propelled motion under the physiological concentration of urea (5 mM), and the motion is less disturbed in the dense tumor matrix. Despite no influence on the endocytosis mechanism, the self-propelled motion and HA-mediated targeting enhance the cellular uptake and cytotoxicity of JNMs. JNMs rapidly release the encapsulated CPT in the acidic endo/lysosomes of tumor cells (pH 5.0) while maintaining their integrity (CTP release <10%) in physiological conditions (pH 7.4) and tumor matrix (pH 6.5). In addition, JNMs are loaded into electrospun fiber fragments (JNM@EF) for intratumoral administration to achieve a high retention and gradual release of JNMs in response to the slightly acidic tumor matrix (pH 6.5). The self-propelled motion promotes the deep penetration and even distribution of JNMs in tumors, dramatically enhancing the antitumor efficacy. Therefore, the launching of nanomotors from intratumoral depots is a feasible strategy to boost the antitumor efficacy via promoting the local accumulation, deep tumor penetration, tumor cell capture and intracellular release of chemotherapeutic drugs.

Size-Tunable DNA-Based Micelles for Deep Tumor Penetration

The dense interstitial structure of tumors often prevents further penetration and internalization into the central region in drug delivery by the enhanced permeability and retention (EPR) effect. In this issue of Chem, Tan et al. report a nucleic-acid-based micelle that undergoes size transformation to resolve the conflict between the EPR effect and spatially uniform tumor penetration.

Large amino acid transporter 1 mediated glutamate modified mesoporous silica nanoparticles for chemophotothermal therapy

Glutamic acid modified Pluronic P123 (P123-G) was synthesized to coat hydrophobic mesoporous silica nanoparticles (PGMSN) aiming to target large amino acid transporter 1 (LAT1) overexpressed cancer cells. We discovered that, once internalized, PGMSN could be transported out of the cells with their cargo, and the exported nanoparticles were then taken up by neighboring cells. This intercellular delivery of particles led to a deeper tumor penetration, presumably through tandem cycles of LAT1 mediated endocytosis and exocytosis. Taking advantage of high drug loading capability of MSN, a kind of cyanine dye Cypate acting as a photothermal converting agent was loaded into MSN along with the chemotherapeutic drug doxorubicin hydrochloride (DOX) to improve the anti-cancer effect by the combination of chemotherapy and photothermal therapy (PTT). Both DOX and Cypate stably dispersed in the pores of MSN, and the coating of P123-G serving as diffusion barrier blocked drug preleakage. The system possessed pH and near-infrared (NIR) light dual-responsive DOX release property. Additionally, PGMSN exhibited targeted PTT effect which strengthened cytotoxic activity of the system due to the enhanced endocytosis. So the deep tumor penetration and targeted PTT effect made PGMSN especially suitable for cancers overexpressing LAT1 receptors.

Light-Triggered PEGylation/dePEGylation of the Nanocarriers for Enhanced Tumor Penetration.

Nanocarriers-derived anticancer therapeutics typically suffers from poor tumor penetration and suboptimal antitumor efficacy. Although PEGylation improves the stability of nanoparticles and prolongs drug circulation, it further increases the size of nanoparticles and adversely affects the tumor penetration. Here, we developed a light-triggered PEGylation/dePEGylation strategy, whereby near-infrared (NIR)-/pH- dual responsive dePEGylation activates iRGD for tumor targeting. The embedded up-conversion nanoparticles (UCNPs) could efficiently convert NIR to UV-vis which cleaved the linker to remove PEG. NIR-induced dePEGylation remarkably improved vascular extravasation of drugs and deep tumor penetration. Therefore, the stimuli-responsive nanocarriers facilitated the tumor-targeted delivery of drugs through blood circulation and enhanced the antitumor effects.

Transferrin Receptor‐Mediated Sequential Intercellular Nanoparticles Relay for Tumor Deep Penetration and Sonodynamic Therapy

AbstractSonodynamic therapy overcomes the tissue penetration barrier of photo‐activated therapeutics, whereas the poor tumor penetration of sonosensitizers largely lowers therapeutic effectiveness. Here, a brand‐new strategy for achieving tumor deep penetration is developed by exploiting the cellular recycling transferrin (Tf). Specifically, a new type of nanosonosensitizer self‐assembled from Tf and organic sonosensitizer protoporphyrin IX is first designed, which exhibits expected biosafety, stability, and ultrasound‐activated cytotoxic reactive oxygen species (ROS) production capability ensuring in vivo administration. More importantly, the nanosonosensitizers inherit the unique transferrin receptor (TfR)‐mediated endocytosis and exocytosis behaviors of Tf, enabling specific binding to TfR‐overexpressed tumor cells and thereafter TfR‐mediated sequential intercellular delivery of nanosonosensitizers. Consequently, tumor deep delivery of sonosensitizers is achieved in TfR‐overexpressed HeLa tumors, which is considerably beneficial for desired tumor‐suppression effect with ROS‐mediated sonodynamic therapy protocol. Such a TfR‐mediated sequential intercellular relay strategy offers an innovative concept for the deep delivery of nanomedicines in tumors.

A novel strategy based on a ligand-switchable nanoparticle delivery system for deep tumor penetration

The ligand-switchable nanocarriers (LSNs) concealed CPPs into the bloodstream and expose them upon entering into the tumor sites, and overall improving the therapeutic effect.

A size-tunable and multi-responsive nanoplatform for deep tumor penetration and targeted combinatorial radio-/chemotherapy

We report a versatile nanoplatform with size tunability, pH-responsiveness, active targeting and radio-/chemotherapeutic features as an efficient tool for tumor therapy.

Impact of Branching on the Solution Behavior and Serum Stability of Starlike Block Copolymers.

The size control of nanomedicines for tumor diagnosis and therapy is of high importance, since it enables or disables deep and sufficient tumor penetration. Amphiphilic star-shaped block copolypept(o)ides offer substantial promise to precisely adjust the hydrophobic core and the hydrophilic corona, independent of each other, and therefore simultaneously control the size dimension in the interesting size range from 10 to 30 nm. To gain access to core-shell structures of such sizes, 3-arm and 6-arm PeptoStars, based on poly(γ- tert-butyloxycarbonyl-l-glutamate)- b-polysarcosine (pGlu(O tBu)- b-pSar), were prepared via controlled living ring-opening polymerization (ROP) of the corresponding N-carboxyanhydrides. Moreover, size exclusion chromatography (SEC) proves the presence of well-defined star shaped polymers with molecular weights from 38 to 88 kg/mol with low polymer dispersities of 1.16 to 1.23. By varying the α-helical peptide core and maintain a constant polysarcosine corona, hydrodynamic size analyses revealed the importance of using a sufficiently large and dense hydrophilic shielding corona to prevent aggregation of the hydrophobic core and obtain uniform-sized spherical-shaped particles with hydrodynamic diameters below 24 nm. Fluorescence correlation spectroscopy (FCS) additionally demonstrates the absence of protein adsorption in human plasma for 6-arm polypept(o)ide stars and thus confirms polysarcosine as stealthlike material.

Hydrophobicity-Adaptive Nanogels for Programmed Anticancer Drug Delivery.

Reconciling the conflicting needs for a prolonged circulation time, enhanced cellular uptake by bulk tumor cells and cancer stem cells (CSCs), and extensive tumor tissue penetration remains a major challenge for current nano drug delivery systems. Here we describe smart poly( N-isopropylacrylamide)-based nanogels with a fast adaptive hydrophobicity to solve these contradictory requirements for enhanced cancer chemotherapy. The nanogels are hydrophilic in the blood to prolong their circulation time. Once they accumulate at tumor sites, they rapidly become hydrophobic in response to tumor extracellular acidity. The adaptive hydrophobicity of the nanogels facilitates tumor accumulation, deep tumor penetration, and efficient uptake by bulk tumor cells and CSCs, resulting in a greater in vivo enrichment in tumor cells and side population cells. Together with lysosomal pH-regulated charge reversal and redox-responsive intracellular drug release, the nanogels escape from lysosomes and release their cargo doxorubicin. Thus, the nanogels significantly improve the in vivo anticancer efficacy and decrease side effects of doxorubicin. Strikingly, the ratio of CSCs is greatly decreased after treatment with the nanogels loaded with doxorubicin. Our current study provides new insights into designing effective anticancer drug delivery systems.

Surface-engineered nanobubbles with pH-/light-responsive drug release and charge-switchable behaviors for active NIR/MR/US imaging-guided tumor therapy

Active drug-loaded nanocarriers have been widely employed as efficient drug delivery systems for tumor theranostics. Herein, we report folate-mediated “all-in-one” nanobubbles for tumor-targeted NIR/MR/US imaging and combined chemo-photothermal therapy. The surface-engineered nanobubbles are constructed from oleylamine-/IR-780-loaded hollow structures, folate and the GdDTPA-BSA@5-FU complex via electrostatic adsorption and further filled with gas after freeze drying. DLS data show that the nanobubbles have a hydrodynamic diameter of 120.41 ± 18.30 nm. TEM observations show a hollow inner cavity and a shell thickness of approximately 10 nm. The relaxivity (r1) of the nanobubbles reaches 16.56 s−1/mM, indicating suitable features for use as a T1-weighted MR contrast agent. Moreover, due to the gas core inside, the nanobubbles are suitable for ultrasound contrast imaging. Interestingly, ξ-potential data and cumulative release measurements demonstrate that the nanobubbles undergo charge-switchable behaviors and pH-/light-sensitive drug-release behaviors after surface engineering, which could facilitate deep tumor penetration and accelerate drug release for efficient killing of cancer cells. In vivo trimodal imaging and chemo-photothermal therapy for MGC-803 tumor-bearing mice reveal selective tumor accumulation, long tumor retention, and enhanced antitumor behaviors. Therefore, the all-in-one nanobubbles could be applied for active tumor-targeting theranostics.

Near-Infrared Laser-Driven in Situ Self-Assembly as a General Strategy for Deep Tumor Therapy.

Nanotherapeutics have encountered some bottleneck problems in cancer therapy, such as poor penetration and inefficient accumulation in tumor site. We herein developed a novel strategy for deep tissue penetration in molecular level and near-infrared (NIR) laser guided in situ self-assembly to solve these challenges. For the proof-of-concept study, we synthesized the polymer-peptide conjugates (PPCs) composed of (i) poly(β-thioester) as thermoresponsive backbone, (ii) functional peptides (cytotoxic peptide and cell-penetrating peptide), and (iii) the NIR molecule with photothermal property. The PPCs in the molecular level with small size (<10 nm) can penetrate deeply into the interior of the tumor at body temperature. Under the irradiation of NIR laser, the temperature rise induced by photothermal molecules led to the intratumoral self-assembly of thermoresponsive PPCs. The resultant spherical nanoparticles can accumulate in tumor and enter cells effectively, inducing cell apoptosis by destroying mitochondria membrane. Through the site-specific size control, a variety of merits of PPCs are realized including deep tumor penetration, enhanced accumulation, and cellular internalization in vivo. Taking advantage of the NIR guided in situ assembly strategy, numerous polymeric or nanoscaled therapeutics with high anticancer activity can be exploited.

Theranostic nanoparticles with tumor-specific enzyme-triggered size reduction and drug release to perform photothermal therapy for breast cancer treatment

Although progress has been indeed made by nanomedicines, their efficacies for cancer treatment remain low, consequently leading to failures in translation to clinic. To improve the drug delivery efficiency, nanoparticles need to change size so as to fully utilize the enhanced permeability and retention (EPR) effect of solid tumor, which is the golden principle of nanoparticles used for cancer treatment. Herein, we employed cationic small-sized red emission bovine serum albumin (BSA) protected gold nanocluster (AuNC@CBSA, 21.06 nm) to both load indocyanine green (ICG) and act as imaging probe to realize theranostic. Then AuNC@CBSA-ICG was fabricated with negatively charged hyaluronic acid (HA) to form AuNC@CBSA-ICG@HA, which was about 200 nm to easily retain at tumor site and could be degraded by tumor-specific hyaluronidase into small nanoparticles for deep tumor penetration. The HA shell also endowed AuNC@CBSA-ICG@HA with actively targeting ability and hyaluronidase-dependent drug release. Furthermore, the quenching and recovery of fluorescence revealed the interaction between ICG and carrier, which was essential for the investigation of pharmacokinetic profiles. No matter in vitro or in vivo, AuNC@CBSA-ICG@HA showed markedly anti-tumor effect, and could suppress 95.0% of tumor growth on mice breast cancer model. All results demonstrated AuNC@CBSA-ICG@HA was potential for breast cancer therapy.

Design of an Amphiphilic iRGD Peptide and Self-Assembling Nanovesicles for Improving Tumor Accumulation and Penetration and the Photodynamic Efficacy of the Photosensitizer

Photodynamic therapy (PDT) is a minimally invasive treatment for many diseases, including infections and tumors. Nevertheless, clinical utilization of PDT is severely restricted due to the shortcomings of the photosensitizers, especially their low water solubility and poor tumor selectivity. iRGD (internalizing RGD, CRGDKGPDC), a nine-unit cyclic peptide, was applied as an active ligand to realize tumor homing and tissue penetration. Herein, we innovatively fabricated a novel OFF-ON mode iRGD-based peptide amphiphile (PA) to self-assemble into spherical nanovesicles to enhance the tumor-targeting and tumor-penetrating efficacy of PDT. To introduce the self-assembling feature into iRGD, a hydrophilic arginine-rich sequence and hydrophobic alkyl chains were sequentially linked to the iRGD motif. A short proline sequence was selected to control the morphology of the self-assembled aggregates. Next, the photosensitizer hypocrellin B (HB) was encapsulated into PA vesicles with a high loading efficiency. The aggregation-caused quenching effect inactivated HB in the PA vesicles; however, the iRGD-peptide-based material was able to be selectively degraded in tumor cells. Thus, the HB fluorescence was recovered to achieve tumor-targeted imaging. This approach endows HB-loaded PA vesicles (HB-PA) with tumor-targeted activation, preferable tumor accumulation, and deep tumor penetration, thus leading to an excellent fluorescence-imaging-guided photodynamic efficacy both in vitro and in vivo. These amphiphilic iRGD aggregates provide a novel strategy for improving the accumulation, penetration, and imaging-guided photodynamic efficacy of photosensitizers.

Ultrasmall gold nanosatellite-bearing transformable hybrid nanoparticles for deep tumor penetration

Since delivering drugs to an entire tumoral region leads to high therapeutic efficacy and good prognosis, achieving deep tumoral penetration of drugs is a major issue in cancer treatment. In this regard, conventional nanomedicines (>50 nm) have shown limitations in cancer therapy, primarily attributed to the heterogeneous distribution of drugs because of the physiological barrier of the tumor interstitial space. To address this issue, we prepared transformable hybrid nanoparticles (TNPs) consisting of a pH-responsive nanocarrier (PEG-PBAE) and doxorubicin (DOX)-conjugated ultrasmall (<3 nm) gold nanoparticles (nanosatellites). It has been shown that PEG-PBAE can serve as a reservoir for nanosatellites and release them in mildly acidic conditions (pH 6.5), mimicking the tumor microenvironment. When DOX-loaded TNPs (DOX-TNPs) were intravenously injected into tumor-bearing mice, they successfully accumulated and dissociated at the extracellular level of the tumor, leading to the disclosure of nanosatellites and free DOX. While the free DOX accumulated in tumor tissue near blood vessels, the deeply diffused nanosatellites were taken up by the tumor cell, followed by the release of DOX via cleavage of pH-responsive ester linkages in the nanosatellites at the intracellular level. Consequently, the DOX-TNPs effectively suppressed tumor growth through improved tumor penetration of DOX, suggesting their promising potential as a cancer nanomedicine. Statement of SignificanceDeep tumor penetration of anticancer drug is an important issue for high therapeutic efficacy. If the drugs cannot reach cancer cells in a sufficient concentration, their effectiveness will be limited. In this regard, conventional nanomedicine showed only modest therapeutic efficacy since they cannot deliver their payloads to the deep site of tumor tissue. This heterogeneous distribution of the drug is primarily attributed to the physiological barriers of the tumor microenvironment, including a dense extracellular matrix. To surmount this challenge, we developed tumor acidity-triggered transformable nanoparticles. By encapsulating doxorubicin-conjugated ultrasmall gold nanosatellites into the nanoparticles, the drug was not significantly bound to genetic materials, resulting in its minimal sequestration near the vasculature and deep tumor penetration. Our strategy could resolve not only the poor penetration issue of the drug but also its restricted tumor accumulation, suggesting the potential as an effective nanotherapeutics.

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

AbstractThe 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.

A Size‐Reducible Nanodrug with an Aggregation‐Enhanced Photodynamic Effect for Deep Chemo‐Photodynamic Therapy

AbstractFluorescent dyes with multi‐functionality are of great interest for photo‐based cancer theranostics. However, their low singlet oxygen quantum yield impedes their potential applications for photodynamic therapy (PDT). Now, a molecular self‐assembly strategy is presented for a nanodrug with a remarkably enhanced photodynamic effect based on a dye‐chemodrug conjugate. The self‐assembled nanodrug possesses an increased intersystem crossing rate owing to the aggregation of dye, leading to a distinct singlet oxygen quantum yield (Φ(1O2)). Subsequently, upon red light irradiation, the generated singlet oxygen reduces the size of the nanodrug from 90 to 10 nm, which facilitates deep tumor penetration of the nanodrug and release of chemodrug. The nanodrug achieved in situ tumor imaging and potent tumor inhibition by deep chemo‐PDT. Our work verifies a facile and effective self‐assembly strategy to construct nanodrugs with enhanced performance for cancer theranostics.

A Size‐Reducible Nanodrug with an Aggregation‐Enhanced Photodynamic Effect for Deep Chemo‐Photodynamic Therapy

Fluorescent dyes with multi-functionality are of great interest for photo-based cancer theranostics. However, their low singlet oxygen quantum yield impedes their potential applications for photodynamic therapy (PDT). Now, a molecular self-assembly strategy is presented for a nanodrug with a remarkably enhanced photodynamic effect based on a dye-chemodrug conjugate. The self-assembled nanodrug possesses an increased intersystem crossing rate owing to the aggregation of dye, leading to a distinct singlet oxygen quantum yield (Φ(1 O2 )). Subsequently, upon red light irradiation, the generated singlet oxygen reduces the size of the nanodrug from 90 to 10 nm, which facilitates deep tumor penetration of the nanodrug and release of chemodrug. The nanodrug achieved in situ tumor imaging and potent tumor inhibition by deep chemo-PDT. Our work verifies a facile and effective self-assembly strategy to construct nanodrugs with enhanced performance for cancer theranostics.