The escape of bladder cancer from immunosurveillance causes monotherapy to exhibit poor efficacy; therefore, designing a multifunctional nanoparticle that boosts programmed cell death and immunoactivation has potential as a treatment strategy. Herein, we developed a facile one-pot coprecipitation reaction to fabricate cluster-structured nanoparticles (CNPs) assembled from Fe3O4 and iron chlorophyll (Chl/Fe) photosensitizers. This nanoassembled CNP, as a multifunctional theranostic agent, could perform red-NIR fluorescence and change the redox balance by the photoinduction of reactive oxygen species (ROS) and attenuate iron-mediated lipid peroxidation by the induction of a Fenton-like reaction. The intravesical instillation of Fe3O4@Chl/Fe CNPs modified with 4-carboxyphenylboronic acid (CPBA) may target the BC wall through glycoproteins in the BC cavity, allowing local killing of cancer cells by photodynamic therapy (PDT)-induced singlet oxygen and causing chemodynamic therapy (CDT)-mediated ferroptosis. An interesting possibility is reprogramming of the tumor microenvironment from immunosuppressive to immunostimulatory after PDT-CDT treatment, which was demonstrated by the reduction of PD-L1 (lower “off” signal to the effector immune cells), IDO-1, TGF-β, and M2-like macrophages and the induction of CD8+ T cells on BC sections. Moreover, the intravesical instillation of Fe3O4@Chl/Fe CNPs may enhance the large-area distribution on the BC wall, improving antitumor efficacy and increasing survival rates from 0 to 91.7%. Our theranostic CNPs not only demonstrated combined PDT-CDT-induced cytotoxicity, ROS production, and ferroptosis to facilitate treatment efficacy but also opened up new horizons for eliminating the immunosuppressive effect by simultaneous PDT-CDT.

The discovery of different binding receptors to allow rapid and high-sensitivity detection via a noninvasive urine test has become the goal for urothelial carcinoma (UC) diagnosis and surveillance. In this study, we developed a new screening membrane receptor platform for bladder cancer cells by integrating surface-enhanced Raman spectroscopy (SERS) with 4-aminothiophenol (4-ATP)-modified AuAg nanohollows upon NIR laser excitation. AuAg nanohollows have an absorption band at ∼630 nm, and slightly off-resonance 785 nm laser excitation is used for minimal photothermal effect. Using the same carbodiimide cross-linker chemistry to conjugate anti-EGFR, transferrin (TF), 4-carboxyphenylboronic acid (CPBA), folic acid (FA), and hyaluronic acid (HA) molecules, by screening the 4-ATP SERS signals intensity, we demonstrated that the targeting efficiency with the cost-effective CPBA molecule is comparable with the conjugation of anti-EGFR antibody to aggressive T24 cancer cells (high-grade), while weak intensity 4-ATP SERS responses to targets were obtained by grade-I RT4 bladder cancer cells, NIH/3T3 fibroblast cells, and SV-HUC1 bladder normal cells. This SERS nanoprobe platform makes primary bladder carcinoma screening from in vitro to ex vivo more straightforward. Our demonstration offers exciting potential for SERS screening of specific receptors on cancer cells of different grades and facilitates new opportunities ranging from surface engineering of SERS material tags to SERS imaging-guided and targeted phototherapy of cancer cells by controlling the laser powers.

Cu@CuO@PSMA polymer nanoparticles (Cu@CuO@polymer NPs) with near-infrared (NIR) absorption were successfully synthesized in a single-step oxidation reaction of Cu@PSMA polymer NPs at 100 °C for 20 min. The shape, structure, and optical properties of the Cu@CuO@polymer NPs were tailorable by controlling the reaction parameters, for example, using the initial Cu@PSMA polymer NP as a template and varying the halide ion content, heating temperature, and reaction time. The Cu@CuO@polymer NPs exhibited robust NIR absorption between 650 and 710 nm and possessed superior oxidation resistance in water and culture media. In vitro assays demonstrated the low cytotoxicity of the Cu@CuO@PSMA polymer NPs to HeLa cells through an improved cell viability, high IC, low injury incidence from the supernatant of the partly dissociated Cu@CuO@PSMA polymer NPs, and minor generation of reactive oxygen species. More importantly, we demonstrated that the inorganic Cu-based nanocomposite [+0.34 V vs normal hydrogen electrode (NHE)] was degradable in an endogenous HO (+1.78 V vs NHE) environment. Cu ions were detected in the urine of mice, which illustrates the possibility of extraction after the degradation of the Cu-based particles. 'After an treatment of the HeLa cells with the Cu@CuO@polymer NPs and a 660 nm light-emitting diode, the photoablation of 50 and 90% cells was observed at NP doses of 20 and 50 ppm, respectively. These results demonstrate that NIR-functional and moderate redox-active Cu@CuO@polymer NPs are potential next-generation photothermal therapy (PTT) nanoagents because of combined features of degradation resistance in the physiological environment, enabling the delivery of efficient PTT, a possibly improved ability to selectively harm cancer cells by releasing Cu ions under high-HO and/or low-pH conditions, and ability to be extracted from the body after biodegradation.

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