Ultra‐Small Iron Oxide Doped Polypyrrole Nanoparticles for In Vivo Multimodal Imaging Guided Photothermal Therapy

Recently, near‐infrared (NIR) absorbing conjugated polymeric nanoparticles have received significant attention in photothermal therapy of cancer. Herein, polypyrrole (PPy), a NIR‐absorbing conjugate polymer, is used to coat ultra‐small iron oxide nanoparticles (IONPs), obtaining multifunctional IONP@PPy nanocomposite which is further modified by the biocompatible polyethylene glycol (PEG) through a layer‐by‐layer method to acquire high stability in physiological solutions. Utilizing the optical and magnetic properties of the yielded IONP@PPy‐PEG nanoparticles, in vivo magnetic resonance (MR) and photoacoustic imaging of tumor‐bearing mice are conducted, revealing strong tumor uptake of those nanoparticles after intravenous injection. In vivo photothermal therapy is then designed and carried out, achieving excellent tumor ablation therapeutic effect in mice experiments. These results promise the use of multifunctional NIR‐absorbing organic‐inorganic hybrid nanomaterials, such as IONP@PPy‐PEG presented here, for potential applications in cancer theranostics.     

Imaging‐Guided pH‐Sensitive Photodynamic Therapy Using Charge Reversible Upconversion Nanoparticles under Near‐Infrared Light

Photodynamic therapy (PDT) based on upconversion nanoparticles (UCNPs) can effectively destroy cancer cells under tissue‐penetrating near‐infrared light (NIR) light. Herein, we synthesize manganese (Mn²⁺)‐doped UCNPs with strong red light emission at ca. 660 nm under 980 nm NIR excitation to activate Chlorin e6 (Ce6), producing singlet oxygen (¹O₂) to kill cancer cells. A layer‐by‐layer (LbL) self‐assembly strategy is employed to load multiple layers of Ce6 conjugated polymers onto UCNPs via electrostatic interactions. UCNPs with two layers of Ce6 loading (UCNP@2xCe6) are found to be optimal in terms of Ce6 loading and ¹O₂ generation. By further coating UCNP@2xCe6 with an outer layer of charge‐reversible polymer containing dimethylmaleic acid (DMMA) groups and polyethylene glycol (PEG) chains, we obtain a UCNP@2xCe6‐DMMA‐PEG nanocomplex, the surface of which is negatively charged and PEG coated under pH 7.4; this could be converted to have a positively charged naked surface at pH 6.8, significantly enhancing cell internalization of nanoparticles and increasing in vitro NIR‐induced PDT efficacy. We then utilize the intrinsic optical and paramagnetic properties of Mn²⁺‐doped UCNPs for in vivo dual modal imaging, and uncover an enhanced retention of UCNP@2xCe6‐DMMA‐PEG inside the tumor after intratumoral injection, owing to the slightly acidic tumor microenvironment. Consequently, a significantly improved in vivo PDT therapeutic effect is achieved using our charge‐reversible UCNP@2xCe6‐DMMA‐PEG nanoparticles. Finally, we further demonstrate the remarkably enhanced tumor‐homing of these pH‐responsive charge‐switchable nanoparticles in comparison to a control counterpart without pH sensitivity after systemic intravenous injection. Our results suggest that UCNPs with finely designed surface coatings could serve as smart pH‐responsive PDT agents promising in cancer theranostics.     

Exosome-Coated 10B Carbon Dots for Precise Boron Neutron Capture Therapy in a Mouse Model of Glioma In Situ

Novel boron-containing carbon dots (BCDs) are designed and prepared for boron neutron capture therapy (BNCT) with superior water solubility and excellent optical property for tracking ¹⁰B in vitro and in vivo. Encapsulation of BCDs using exosomes (Exos) from macrophages yields BCD–Exos of ≈100 nm. Fluorescent imaging shows that the BCD–Exos are internalized and distributed around the nuclei of U-87-MG glioma cells. BCD–Exos are also verified to cross the blood–brain barrier and significant accumulation in tumor tissue of the orthotopic U-87-MG glioma tumor-bearing mice model 4 h after administration. Using inductively coupled plasma mass spectrometry (ICP-MS), it is detected that ¹⁰B in tumor tissue is 107.07 ± 1.58 ppm, and T/N ratios are enhanced from 2.03 ± 0.08 of boron phenylalanine (BPA) to 5.28 ± 0.29 of the BCD–Exos. In BNCT, the neutron radiation dose is 8.40 ± 0.12 Gy when a 500 mg kg^{−1 10}B dosage is given. Finally, there is a prominent BNCT effect of the BCD–Exos-treated brain glioma in the mice model, and the survival ratio is 100% at the end of the experiment. The excellent curative effect of BNCT using BCD–Exos to brain glioma is achieved through adjusted biodistribution of boron in the cancer cell, enhanced T/N ratios, and the precise match between boron and neutron exposure in the site of the tumor in vivo with fluorescence imaging of BCD–Exos.     

Colorectal Cancer Diagnosis Using Enzyme‐Sensitive Ratiometric Fluorescence Dye and Antibody–Quantum Dot Conjugates for Multiplexed Detection

A rapid and accurate molecular fluorescence imaging technique will greatly reduce cancer mortality by overcoming the detection limit of the naked eye in colonoscopy. Two imaging probes are reported that can be co‐used for colonoscopic diagnosis: a fluorescent molecular probe, cresyl violet–glutamic acid derivative, that ratiometrically switches between two fluorescent colors in response to the enzyme activity of λ‐glutamyltranspeptidase and an antibody quantum dot probe that is a conjugate of biocompatible AgInS₂ quantum dot with matrix metalloproteinase 14 antibodies. Validity of the probes is confirmed using human colon cancer cell lines, ex vivo mouse model tissues, and patient tumor colon tissues in which the tumor lesions are well‐visualized in less than five minutes. Co‐application of the two probes onto fresh colon tissues affords accurate visualization of carcinomas and also hyperplasia and adenoma regions. Fresh human colon adenoma tissues are also valuated, where the two probes show complementary diagnoses of cancer. Two‐photon microscopy shows the time‐dependent depth profiles of the two probes. Both rapidly permeate and populate most at 10–20 µm from the surface. Extensive toxicity studies are performed for the two probes at cellular level and also at the organ level using a small animal model.     

PEGylated Polypyrrole Nanoparticles Conjugating Gadolinium Chelates for Dual‐Modal MRI/Photoacoustic Imaging Guided Photothermal Therapy of Cancer

Polypyrrole nanoparticles conjugating gadolinium chelates were successfully fabricated for dual‐modal magnetic resonance imaging (MRI) and photoacoustic imaging guided photothermal therapy of cancer, from a mixture of pyrrole and pyrrole‐1‐propanoic acid through a facile one‐step aqueous dispersion polymerization, followed by covalent attachment of gadolinium chelate, using polyethylene glycol as a linker. The obtained PEGylated poly­pyrrole nanoparticles conjugating gadolinium chelates (Gd‐PEG‐PPy NPs), sized around around 70 nm, exhibited a high T₁ relaxivity coefficient of 10.61 L mm ^?1 s^?1, more than twice as high as that of the relating free Gd³⁺ complex (4.2 L mm ^–1 s^?1). After 24 h intravenous injection of Gd‐PEG‐PPy NPs, the tumor sites exhibited obvious enhancement in both T₁‐weighted MRI intensity and photoacoustic signal compared with that before injection, indicating the efficient accumulation of Gd‐PEG‐PPy NPs due to the introduction of the PEG layer onto the particle surface. In addition, tumor growth could be effectively inhibited after treatment with Gd‐PEG‐PPy NPs in combination with near‐infrared laser irradiation. The passive targeting and high MRI/photo­acoustic contrast capability of Gd‐PEG‐PPy NPs are quite favorable for precise cancer diagnosing and locating the tumor site to guide the external laser irradiation for photothermal ablation of tumors without damaging the surrounding healthy tissues. Therefore, Gd‐PEG‐PPy NPs may assist in better monitoring the therapeutic process, and contribute to developing more effective “personalized medicine,” showing great potential for cancer diagnosis and therapy.     

A Strategy of Limited-Space Controlled Aggregation for Generic Enhancement of Drug Loading Capability

A prevalent problem of magnetic resonance imaging (MRI) contrast agents (CAs) for drug loading applications is easy aggregation. The major concern of hollow mesoporous organosilica nanoparticles (HMONs) is hard control of untimely drug leakage. To overcome both problems, a new strategy of limited-space controlled aggregation for generic enhancement of drug loading capability is proposed. Typically, MRI CAs of exceedingly small gadolinium oxide nanoparticle (GO) and Gd poly(acrylic acid) macrochelate (GP) are exploited to load doxorubicin (D) in HMONs hollow core. The GO@D@HMONs and GP@D@HMONs without precipitation formation display much higher drug loading contents (33.0 ± 4.9%, 39.6 ± 4.0%) than GO@D and GP@D with serious precipitation generation (4.7 ± 0.5% and 14.7 ± 3.4%), which can be ascribed to the generation of GO@D and GP@D aggregates with larger sizes in HMONs hollow core than the pore size of HMONs preventing the drug leakage. The tumor microenvironment (TME)-specific glutathione (GSH)-triggered degradation of HMONs and the controlled drug release behaviors reinforce the chemotherapeutic efficacy and alleviate side effects on normal cells/tissues. The GSH-activatable T₁-MRI is favorable to high contrast tumor imaging. Overall, the strategy of limited-space controlled aggregation is promising for generic enhancement of drug loading capability of MRI CAs, realizing MRI-guided high-performance cancer treatments.     

A Chlorotoxin-Directed Diselenide-Bridged Tumor-Homing Persistent Luminescence Nanoprobes Mediating Inhibition of Oxidative Phosphorylation for Long-Term Near-Infrared Imaging and Therapy of Glioblastoma

Glioblastoma (GBM) is the most prevailing malignant primary brain tumor, and the precise diagnosis of GBM has always been a challenge. Gboxin is a recently developed drug efficiently inhibiting the oxidative phosphorylation in GBM cells, and both the chlorotoxin (CLTX) and GBM cell membrane coating are capable of GBM targeting and tumor homing. Herein, the near-infrared (NIR) persistent luminescence (PL) nanoparticle, CUDZG, with a dual function of imaging and therapy is developed based on ZnGa₂O₄:Cr³⁺,Sn⁴⁺. CUDZG exhibits superior rechargeable NIR PL for at least 48 h with excellent tissue penetration in vivo, which enables the longstanding autofluorescence-free imaging of the orthotopic GBM. The tumor growth of both the orthotropic and subcutaneous GBM-bearing mice are significantly suppressed by CUDZG. This is the first-time report of 1) the integration of CLTX and cell membrane coating for drug delivery, 2) diselenide-based trigger release for anti-GBM therapy, and 3) the systemic delivery of Gboxin. This study also offers an example of the highly promising blood-brain penetrable drug carriers for precise diagnosis and therapy of central nervous system diseases.     

Conjugated Polymer Based Nanoparticles as Dual‐Modal Probes for Targeted In Vivo Fluorescence and Magnetic Resonance Imaging

A facile strategy is developed to synthesize dual‐modal fluorescent‐magnetic nanoparticles (NPs) with surface folic acid by co‐encapsulation of a far‐red/near‐infrared (FR/NIR)‐emissive conjugated polymer (PFVBT) and lipid‐coated iron oxides (IOs) into a mixture of poly(lactic‐co‐glycolic‐acid)‐poly(ethylene glycol)‐folate (PLGA‐PEG‐FOL) and PLGA. The obtained NPs exhibit superparamagnetic properties and high fluorescence, which indicates that the lipid coated on IOs is effective at separating the conjugated polymer from IOs to minimize fluorescence quenching. These NPs are spherical in shape with an average diameter of ≈180 nm in water, as determined by laser light scattering. In vitro studies reveal that these dual‐modal NPs can serve as an effective fluorescent probe to achieve targeted imaging of MCF‐7 breast cancer cells without obvious cytotoxicity. In vivo fluorescence and magnetic resonance imaging results suggest that the NPs are able to preferentially accumulate in tumor tissues to allow dual‐modal detection of tumors in a living body. This demonstrates the potential of conjugated polymer based dual‐modal nanoprobes for versatile in vitro and in vivo applications in future.     

pH‐ and NIR Light‐Responsive Micelles with Hyperthermia‐Triggered Tumor Penetration and Cytoplasm Drug Release to Reverse Doxorubicin Resistance in Breast Cancer

The acquisition of multidrug resistance (MDR) is a major hurdle for the successful chemotherapy of tumors. Herein, a novel hybrid micelle with pH and near‐infrared (NIR) light dual‐responsive property is reported for reversing doxorubicin (DOX) resistance in breast cancer. The hybrid micelles are designed to integrate the pH‐ and NIR light‐responsive property of an amphiphilic diblock polymer and the high DOX loading capacity of a polymeric prodrug into one single nanocomposite. At physiological condition (i.e., pH 7.4), the micelles form compact nanostructure with particle size around 30 nm to facilitate blood circulation and passive tumor targeting. Meanwhile, the micelles are quickly dissociated in weakly acidic environment (i.e., pH ≤ 6.2) to release DOX prodrug. When exposed to NIR laser irradiation, the hybrid micelles can trigger notable tumor penetration and cytosol release of DOX payload by inducing tunable hyperthermia effect. In combination with localized NIR laser irradiation, the hybrid micelles significantly inhibit the growth of DOX‐resistant MCF‐7/ADR breast cancer in an orthotopic tumor bearing mouse model. Taken together, this pH and NIR light‐responsive micelles with hyperthermia‐triggered tumor penetration and cytoplasm drug release can be an effective nanoplatform to combat cancer MDR.     

Gold Nanorods Electrostatically Binding Nucleic Acid Probe for In Vivo MicroRNA Amplified Detection and Photoacoustic Imaging‐Guided Photothermal Therapy

Developing a comprehensive platform which has both diagnosis and therapeutic strategies is necessary for efficient tumor treatment. In this work, a F uel I mproved micro R NA E xplorer (FIRE) probe with signal amplification capability is designed for sensitive detection of microRNA‐21 (miR‐21), which is upregulated in most tumor cells. Besides, FIRE could be loaded by polyethylenimine (PEI)‐modified gold nanorods (AuNR‐PEI) via facile electrostatic interaction, which could avoid the complicated processes commonly used to covalently conjugate nucleic acid probes onto AuNRs. The as‐fabricated AuNR‐PEI/FIRE system could efficiently distinguish tumor cells from non‐tumor cells. The fluorescence signals in MCF‐7 breast carcinoma and HeLa cervical carcinoma cells treated with AuNR‐PEI/FIRE are enhanced 7‐ and 4.5‐fold, respectively, compared with non‐amplification system. AuNR‐PEI/FIRE improves tumor detection ability in vivo and exhibits excellent tumor inhibition efficacy under the fluorescence imaging and photoacoustic imaging guided photothermal therapy. This is the first time to utilize the combined application of amplified nucleic acid detection and photothermal effect derived from gold nanorods together with PA imaging in a facile manner to provide a promising theranostic strategy for accurate diagnosis and tumor therapy.     

Targeted Tumor Hypoxia Dual‐Mode CT/MR Imaging and Enhanced Radiation Therapy Using Dendrimer‐Based Nanosensitizers

The efficacy of radiation therapy (RT) is often limited by the poor response of hypoxia inside most solid tumors. The development of a theranostic nanoplatform for precision‐imaging‐guided sensitized RT for tumor hypoxia is still challenging. Herein, the creation of hypoxia‐targeted dendrimer‐entrapped gold nanoparticles complexed with gadolinium(III) (Gd‐Au DENPs‐Nit) for dual‐mode CT/MR imaging and sensitized RT of hypoxic tumors is reported. In this work, generation 5 poly(amidoamine) dendrimers are partially conjugated with Gd(III) chelator, entrapped with Au nanoparticles, and conjugated with hypoxia‐targeting agent nitroimidazole via a polyethylene glycol linker, and ending with chelation of Gd(III) and conversion of their leftover amine termini to acetamides. The designed dendrimer‐based nanohybrids with 3.2 nm Au cores exhibit an excellent X‐ray attenuation effect, acceptable r₁ relaxivity (1.32 mM^?1 s^?1), and enhanced cellular uptake in hypoxic cancer cells, affording efficient dual‐mode CT/MR imaging of tumor hypoxia. Under X‐ray irradiation, the Gd‐Au DENPs‐Nit nanohybrids can produce reactive oxygen species, promote DNA damage, and prevent DNA repair, facilitating sensitized RT of hypoxic cancer cells in vitro and tumor hypoxia in vivo. The developed hypoxia‐targeted dendrimer‐based nanohybrids may be employed as both contrast agents and nanosensitizers for precision tumor hypoxia imaging and sensitized tumor RT.     

Engineering of Multifunctional Nano‐Micelles for Combined Photothermal and Photodynamic Therapy Under the Guidance of Multimodal Imaging

The integration of diagnostic and therapeutic functionalities on a single theranostic nano‐system holds great promise to enhance the accuracy of diagnosis and improve the efficacy of therapy. Herein, a multifunctional polymeric nano‐micelle system that contains a photosensitizer chlorin e6 (Ce6) is successfully fabricated, at the same time serving as a chelating agent for Gd³⁺, together with a near‐infrared (NIR) dye, IR825. With a r₁ relativity 7 times higher than that of the commercial agent Magnevist, strong fluorescence offered by Ce6, and high NIR absorbance attributed to IR825, these theranostic micelles can be utilized as a contrast agent for triple modal magnetic resonance (MR), fluorescence, and photoacoustic imaging of tumors in a mouse model. The combined photothermal and photodynamic therapy is then carried out, achieving a synergistic anti‐tumor effect both in vitro and in vivo. Different from single photo treatment modalities which only affect the superficial region of the tumor under mild doses, the combination therapy at the same dose using this agent is able to induce significant damage to both superficial and deep parts of the tumor. Therefore, this work presents a polymer based theranostic platform with great potential in multimodal imaging and combination therapy of cancer.     

Covalent Functionalization of Multi‐walled Carbon Nanotubes with a Gadolinium Chelate for Efficient T1‐Weighted Magnetic Resonance Imaging

Given the promise of carbon nanotubes (CNTs) for photothermal therapy, drug delivery, tissue engineering, and gene therapy, there is a need for non‐invasive imaging methods to monitor CNT distribution and fate in the body. In this study, non‐ionizing whole‐body high field magnetic resonance imaging (MRI) is used to follow the distribution of water‐dispersible non‐toxic functionalized CNTs administrated intravenously to mice. Oxidized CNTs are endowed with positive MRI contrast properties by covalent functionalization with the chelating ligand diethylenetriaminepentaacetic dianhydride (DTPA), followed by chelation to Gd³⁺. The structural and magnetic properties, MR relaxivities, cellular uptake, and application for MRI cell imaging of Gd‐CNTs in comparison to the precursor oxidized CNTs are evaluated. Despite the intrinsic T₂ contrast of oxidized CNTs internalized in macrophages, the anchoring of paramagnetic gadolinium onto the nanotube sidewall allows efficient T₁ contrast and MR signal enhancement, which is preserved after CNT internalization by cells. Hence, due to their high dispersibility, Gd‐CNTs have the potential to produce positive contrast in vivo following injection into the bloodstream. The uptake of Gd‐CNTs in the liver and spleen is assessed using MRI, while rapid renal clearance of extracellular Gd‐CNTs is observed, confirming the evidences of other studies using different imaging modalities.     

Targeting CXCR4–CXCL12 Axis for Visualizing,Predicting, and Inhibiting Breast Cancer Metastasis with Theranostic AMD3100–Ag2S Quantum Dot Probe

Breast cancer metastasis remains the primary cause of death and efforts to predict and reduce metastatic risk are particularly appealing. CXC chemokine receptor 4 (CXCR4) is reported as a specific metastasis due to its chemotactic homing to CXCL12. Herein, conjugation of a CXCR4 antagonist, AMD3100, to a fluorescent silver sulfide quantum dot (Ag₂S) core (QD‐AMD) allows accurate detection of CXCR4 expression in tumor. Particularly, the probe precisely distinguishes highly metastatic breast cancer cells from those of lower metastatic ability. Longitudinal in vivo imaging predicts at early stages that the high CXCR4 expressing orthotopic 4T1 tumor would subsequently metastasize to lungs 14 d after tumor inoculation, while no metastasis forms from the low CXCR4 expressing MCF‐7 tumor. Correlative measurements find that the CXCL12 levels in lung increase with tumor progression. Perturbations of either CXCR4 on tumor cells by QD‐AMD or CXCL12 in the lungs by antibody successfully inhibit cancer metastasis. Intravenous injection of QD‐AMD in primary 4T1 tumor model effectively reduces lung metastasis. More importantly, due to the intrinsic photothermal effect, the metastatic spread is more thoroughly abrogated along with substantial shrinkage of primary tumor. Altogether, the probe is promising to detect, predict, and inhibit the metastatic spread of breast tumor.     

Tantalum Sulfide Nanosheets as a Theranostic Nanoplatform for Computed Tomography Imaging‐Guided Combinatorial Chemo‐Photothermal Therapy

Near‐infrared (NIR)‐absorbing metal‐based nanomaterials have shown tremendous potential for cancer therapy, given their facile and controllable synthesis, efficient photothermal conversion, capability of spatiotemporal‐controlled drug delivery, and intrinsic imaging function. Tantalum (Ta) is among the most biocompatible metals and arouses negligible adverse biological responses in either oxidized or reduced forms, and thus Ta‐derived nanomaterials represent promising candidates for biomedical applications. However, Ta‐based nanomaterials by themselves have not been explored for NIR‐mediated photothermal ablation therapy. In this work, an innovative Ta‐based multifunctional nanoplatform composed of biocompatible tantalum sulfide (TaS₂) nanosheets (NSs) is reported for simultaneous NIR hyperthermia, drug delivery, and computed tomography (CT) imaging. The TaS₂ NSs exhibit multiple unique features including (i) efficient NIR light‐to‐heat conversion with a high photothermal conversion efficiency of 39%, (ii) high drug loading (177% by weight), (iii) controlled drug release triggered by NIR light and moderate acidic pH, (iv) high tumor accumulation via heat‐enhanced tumor vascular permeability, (v) complete tumor ablation and negligible side effects, and (vi) comparable CT imaging contrast efficiency to the widely clinically used agent iobitridol. It is expected that this multifunctional NS platform can serve as a promising candidate for imaging‐guided cancer therapy and selection of cancer patients with high tumor accumulation.     

Gold Nanoframeworks with Mesopores for Raman–Photoacoustic Imaging and Photo‐Chemo Tumor Therapy in the Second Near‐Infrared Biowindow

Gold‐based nanostructures with tunable wavelength of localized surface plasmon resonance (LSPR) in the second near‐infrared (NIR‐II) biowindow receive increasing attention in phototheranostics. In view of limited progress on NIR‐II gold nanostructures, a particular liposome template‐guided route is explored to synthesize novel gold nanoframeworks (AuNFs) with large mesopores (≈40 nm) for multimodal imaging along with therapeutic robustness. The synthesized AuNFs exhibit strong absorbance in NIR‐II region, affording their capacity of NIR‐II photothermal therapy (PTT) and photoacoustic (PA) imaging for deep tumors. Functionalization of AuNFs with hyaluronic acid (HA) endows the targeting capacity for CD44‐overexpressed tumor cells while gatekeeping doxorubicin (DOX) loaded into mesopores. Conjugation of Raman reporter 4‐aminothiophenol (4‐ATP) onto AuNFs yields a surface‐enhanced Raman scattering (SERS) fingerprint for Raman spectroscopy/imaging. In vivo evaluation of HA‐4‐ATP‐AuNFs‐DOX on tumor‐bearing xenografts demonstrates its high efficacy in eradication of solid tumors in NIR‐II under PA–Raman dual image‐guided photo‐chemotherapy. Thus, current AuNFs offer versatile capabilities for phototheranostics.     

Bioinspired Nanoparticles with NIR‐Controlled Drug Release for Synergetic Chemophotothermal Therapy of Metastatic Breast Cancer

Optimal nanosized drug delivery systems (NDDS) require long blood circulation and controlled drug release at target lesions for efficient anticancer therapy. Red blood cell (RBC) membrane‐camouflaged nanoparticles (NPs) can integrate flexibility of synergetic materials and highly functionality of RBC membrane, endowed with many unique advantages for drug delivery. Here, new near‐infrared (NIR)‐responsive RBC membrane‐mimetic NPs with NIR‐activated cellular uptake and controlled drug release for treating metastatic breast cancer are reported. An NIR dye is inserted in RBC membrane shells, and the thermoresponsive lipid is employed to the paclitaxel (PTX)‐loaded polymeric cores to fabricate the RBC‐inspired NPs. The fluorescence of dye in the NPs can be used for in vivo tumor imaging with an elongated circulating halftime that is 12.3‐folder higher than that of the free dye. Under the NIR laser stimuli, the tumor cellular uptake of NPs is significantly enhanced to 2.1‐fold higher than that without irradiation. The structure of the RBC‐mimetic NPs can be destroyed by the light‐induced hyperthermia, triggered rapid PTX release (45% in 30 min). These RBC‐mimetic NPs provide a synergetic chemophotothermal therapy, completely inhibited the growth of the primary tumor, and suppress over 98% of lung metastasis in vivo, suggesting it to be an ideal NDDS to fight against metastatic breast cancer.     

Positive and Negative Lattice Shielding Effects Co‐existing in Gd (III) Ion Doped Bifunctional Upconversion Nanoprobes

Gadolinium (Gd) doped upconversion nanoparticles (UCNPs) have been well documented as T₁‐MR and fluorescent imaging agents. However, the performance of Gd³⁺ ions located differently in the crystal lattice still remains debatable. Here, a well‐designed model was built based on a seed‐mediated growth technique to systematically probe the longitudinal relaxivity of Gd³⁺ ions within the crystal lattice and at the surface of UCNPs. We found, for the first time, a nearly 100% loss of relaxivity of Gd³⁺ ions buried deeply within crystal lattices (> 4 nm), which we named a “negative lattice shielding effect” (n‐LSE) as compared to the “positive lattice shielding effect” (p‐LSE) for the enhanced upconversion fluorescent intensity. As‐observed n‐LSE was further found to be shell thickness dependent. By suppressing the n‐LSE as far as possible, we optimized the UCNPs' structure design and achieved the highest r₁ value (6.18 mM^?1s^?1 per Gd³⁺ ion) among previously reported counterparts. The potential bimodal imaging application both in vitro and in vivo of as‐designed nano‐probes was also demonstrated. This study clears the debate over the role of bulk and surface Gd³⁺ ions in MRI contrast imaging and paves the way for modulation of other Gd‐doped nanostructures for highly efficient T₁‐MR and upconversion fluorescent bimodal imaging.     

Tunable Förster Resonance Energy Transfer in Colloidal Nanoparticles Composed of Polycaprolactone‐Tethered Donors and Acceptors: Enhanced Near‐Infrared Emission and Compatibility for In Vitro and In Vivo Bioimaging

A near‐infrared (NIR) fluorescent donor/acceptor (D/A) nanoplatform based on Förster resonance energy transfer is important for applications such as deep‐tissue bioimaging and sensing. However, previously reported D/A nanoparticles (NPs) often show limitations such as aggregation‐induced fluorescence quenching and poor interfacial compatibility that reduces the efficiency of the energy transfer and also leads to leaching of the small molecular fluorophores from the NP matrix. Here highly NIR‐fluorescent D/A NPs with a fluorescence quantum yield as high as 46% in the NIR region (700–850 nm) and robust optical stability are reported. The hydrophobic core of each NP is composed of donor and acceptor moieties both of which are tethered with polycaprolactone (PCL), while the hydrophilic corona is composed of poly[oligo(ethylene glycol) methyl ether methacrylate] to offer colloidal stability and “stealthy” effect in aqueous media. The PCL matrix in each colloidal NP not only offers biocompatibility and biodegradability but also minimizes the aggregation‐caused fluorescence quenching of D/A chromophores and prevents the leakage of the NIR fluorophores from the NPs. In vivo imaging using these NIR NPs in live mice shows contrast‐enhanced imaging capability and efficient tumor‐targeting through enhanced permeability and retention effect.