Application of 1064 nm activatable NIR-IIa fluorescence imaging (FI) and NIR-II photothermal therapy (PTT) results in high-resolution imaging and good deep-tissue therapy, respectively. Combining NIR-IIa FI with NIR-II PTT may allow precise diagnosis guided efficient treatment of deep-tissue tumors. However, designing a 1064 activatable theranostic nanoplatform using a single dye for both NIR-IIa FI and NIR-II PTT is a challenge. Herein, we synthesized squaraine-based semiconducting polymer nanoparticles (PSQPNs-DBCO) that were excited by a 1064 nm laser for precise NIR-IIa fluorescence imaging guided NIR-II PTT treatment. Combined with bioorthogonal labeling technology, the PSQPNs-DBCO largely accumulated in the tumor section, extremely enhancing signal-to-background ratio (SBR) of imaging and NIR-II PTT efficiency of tumor in live colorectal-bearing animals.

Up to now, limited tumor penetration and poor therapeutic efficiency of drug-loaded nanoparticles are still the major challenges in nanomedicines for cancer chemotherapy. In photodynamic therapy, photosensitizers are often used to generate cytotoxic reactive oxygen species to kill cancer cells. Here, we report a kind of ROS-responsive nanoparticles with light-triggered size-reducing for enhanced tumor penetration and in vivo drug delivery to improve therapeutic efficiency. The nanoparticles were constructed by the self-assembly of an amphiphilic hyperbranched polyphosphoester containing thioketal units and photosensitizers, which is synthesized through the self-condensing ring-opening polymerization of a novel cyclic phosphate monomer and then end-capped with photosensitizer Chlorin e6. These nanoparticles have an initial averaged diameter of ∼210 nm, which can be used as drug carriers to load camptothecin with relatively stable in blood circulation. The CPT-loaded nanoparticles can be concentrated in tumor tissues through the long blood circulation and enhanced permeability and retention effect. Upon 660 nm laser irradiation on tumor tissues, the Ce6s in nanoparticles can effectively generate ROS to kill cancer cells meanwhile cleave the thioketal units to sequentially reduce the size of nanoparticles, which facilitate them more efficient tumor penetration with a programmable release of CPT. Both in vitro and in vivo studies confirmed the above results. Such ROS-responsive nanoparticles with light-triggered size-reducing provided a feasible approach to improve drug tumor penetration and achieve satisfied therapeutic efficacy.

The oral administration route is popular with T2DM patients because they need convenience in lifelong medication. At present, oral Exenatide is not available on the market and therefore the relevant studies are valuable. Herein, we constructed a novel dual cholic acid-functionalized nanoparticle for oral delivery of Exenatide, which was based on the functionalized materials of deoxycholic acid-low molecular weight protamine and glycocholic acid-poly (ethylene glycol)-b-polysialic acid. The hydrophobic deoxycholic acid strengthened the nanoparticles and the hydrophilic glycolic acid targeted to specific transporter. We first condensed Exenatide-Zn2+ complex with deoxycholic acid-low molecular weight protamine to prepare nanocomplexes with ζ-potentials of +8 mV and sizes of 95 nm. Then, we used glycocholic acid-poly (ethylene glycol)-b-polysialic acid copolymers masking the positive charge of nanocomplexes to prepare nanoparticles with negative charges of -22 mV and homogeneous sizes of 140 nm. As a result, this dual cholic acid-functionalized nanoparticle demonstrated enhanced uptake and transport of Exenatide, and a special targeting to apical sodium-dependent cholic acid transporter in vitro. Moreover, in vivo studies showed that the nanoparticle effectively accumulated in distal ileum, raised the plasma concentration of Exenatide, prolonged hypoglycemic effect, reduced blood lipid levels, and lightened organ lesions.

Colon cancer is emerging as one of the most prevalent cancers globally. Oral colonic drug delivery systems have attracted considerable attention in the treatment of orthotopic colon cancer due to their superior properties. However, the particularity and complexity of the gastrointestinal structure are a hindrance to the safe delivery of drugs to the target site of the colon tumor. Herein, to achieve an effective delivery system specifically targeting the colon, we designed paclitaxel (PTX)-loaded oral colon double-targeted nanoparticles using polylactic acid-polyethyleneimine (PLA-PEI) and hyaluronic acid-inulin (HA-IN). IN is enzyme sensitive and hardly degraded in the upper digestive tract; as such, it can ensure the safe delivery of nanoparticles to the colon. The "IN shell" is degraded by colon-specific bacteria at the colon site. The exposed HA not only promotes intestinal mucosal crossing of nanoparticles, but also acts as the target of CD44 and plays an active targeting role in tumor tissues. The action of the proton sponge effect of PEI induces the successful release of the nanoparticle. The prepared nanoparticles have a negative charge of -19.5 ± 1.2 mV and a size of 176.7 ± 0.3 nm with a narrow PDI of 0.148 ± 0.004. C26 cells were used for in vitro anticancer studies, including fluorescence staining and flow cytometry, and to explore inhibition of proliferation. The analysis demonstrated that the nanoparticles were more efficiently taken up by cancer cells, exhibiting greater cytotoxicity and apoptosis-inducing ability compared to free drugs. Moreover, in vivo studies revealed that the nanoparticles could remain in vivo for 24 h and accumulate at the tumor site. These data provide evidence of the therapeutic effect on orthotopic colon cancer. Also, safety evaluation results demonstrated that PLA-PEI/HA-IN is a safe drug delivery vector, therefore, holds great promise as a new therapeutic strategy for orthotopic colon cancer treatment.

Gasotransmitters with their cytotoxicity in high concentration have become the focus of attention. For such concentration depended therapy, how to effectively deliver gases and precisely control gases release to the lesion as well as combine them with other therapy to achieve precise therapeutics is still a big challenge. Herein, we realize single near-infrared (NIR) laser-initiated nitric oxide (NO) therapy/photothermal therapy (PTT) using semiconducting polymer nanoparticles (SPNs, PFTDPP) combing s-nitrosothiol groups (the NO donor, SNAP). By the good photothermal conversion effect of SPNs, NIR laser energy can be spatio-temporally controlled to convert into heat to decompose s-nitrosothiol. Meanwhile, considering the accompanied PTT produced by photothermal, we can easily and precisely conduct a dual therapy (NO therapy/PTT) under single NIR laser irradiation. Additionally, semiconducting polymer with its structural modifiability and spectral adjustability can provide a second NIR window & photoacoustic (NIR II/PA) imaging for guiding photothermal initiated NO/photothermal therapy. PFTDPP showed a high photothermal conversion efficiency of 48% and good dual-mode imaging signals (NIR-II/photoacoustic). Cellular test illustrated that NO combined photothermal presented more prominent cytotoxicity than any one of them individually. As the tumor pinpointed in vivo by dual-mode imaging (NIR II/PA), this nanotheranostics provided a tumor inhibition of 77%. Consequently, such phototheranostics produced a new design thought for effectively deliver and precisely controlled release of drugs for oncology. And also, it expanded the application range of gasotransmitters combined therapy that shall have a promising application foreground.

Photodynamic therapy (PDT) combined with hypoxia-activated prodrugs to overcome hypoxia environment has been recently explored as a promising clinical modality for cancer therapy. Nevertheless, delivering these two therapeutic agents together to different tumour areas that possess a number of biological barriers remains a considerable challenge. Herein, we used the semiconducting polyelectrolyte-based zwitterionic photosensitizer (PFNS) to modify the surface of upconversion nanoparticles (NPs) and prepare near-infrared (NIR) light-responsive PDT agents (UCNP@PFNS). A pH-sensitive Mn-Ca3(PO4)2 (MnCaP) layer was further coated onto UCNP@PFNS with the hypoxia-activated prodrug AQ4N incorporated inside. The final nanocomposites exhibited a diameter of 73 nm with high stability in the blood and a remarkably enhanced permeability and retention (EPR) effect in tumours. Importantly, when these nanoparticles reached the tumour site, the acidic tumour microenvironment (pH 6.5-6.8) decomposed the MnCaP layer, releasing both UCNP@PFNS (30 nm) and AQ4N. The relatively small size of UCNP@PFNS and AQ4N satisfied the different distribution requirements in tumour and achieved a high therapeutic effect, thereby reaching an inhibition rate of as high as 83%. In addition, Mn2+ ions can be released during the decomposition of CaP, leading to a significantly increased magnetic resonance (MR) signal in the tumour site. Overall, we report a nanoparticle guided by MRI and fluorescence imaging possesses of tandem active pattern of PDT and chemotherapy, which is promising for future clinical diagnosis and treatment.

Highly specific and effective cancer phototherapy remains as a great challenge. Herein, a smart nanoplatform (TENAB NP) sequentially responsive to light, low pH and hypoxia is demonstrated for multi-mode imaging guided synergistic cancer therapy with negligible skin phototoxicity. Upon 808-nm laser irradiation, TENAB NPs can generate hyperthermia to melt the phase change material (PCM-LASA) coat and thereafter release chemo-drug tirapazamine (TPZ). Meanwhile, under acidic pH, photosensitizer ENAB would turn "off" its charge-transfer state, generating prominent 1O2 for photodynamic therapy (PDT) and heat for photothermal therapy (PTT), respectively. Accompanied with PDT-induced hypoxia, the released TPZ can be activated into its cytotoxic form for tumor cells killing. Notably, owing to phase change material LASA coat and ENAB's pH sensitivity, TENAB NPs show negligible photosensitization to skin and normal tissues. As the multi-stimuli responsive mechanism, TENAB NPs demonstrate a promising future in cancer photo-chemo theranostics with excellent skin protection.

Current phototheranostics is still encountering various impediments, which causes complicated and prolonged therapy, and increases unnecessary side effects and systemic toxicity to patients. Herein, mitochondria-targeting one-for-all phototheranostic nanoparticles based on single-component organic molecule were designed and fabricated. After being irradiated with a single 808 nm laser, outstanding second near-infrared (NIR-II) fluorescence signals (with a high fluorescence quantum yield of 2.2% in water) were obtained for NIR-II fluorescence imaging, which could efficiently locate tumor and real-time monitor the therapeutic process. Moreover, such nanoparticles also presented superb photothermal conversion efficiency (39.6%) and singlet oxygen yield (2.3%, almost 12 times higher than clinical NIR dye indocyanine green) under 808 nm laser illumination, which could produce both potent hyperthermia and abundant singlet oxygen, resultantly leading to the mitochondrial dysfunction and further cell apoptosis. Both in vitro and in vivo investigations demonstrated that such nanoagents displayed significantly tumor theranostic efficacy, resulting from single 808 nm laser triggered high performance NIR-II fluorescence imaging guided mitochondria-targeting phototherapy. It was noteworthy that only a single-dose injection and 808 nm laser irradiation were employed during in vivo treatment. We believe that the phototheranostic nanoparticles developed in this work will open up a new dimension in cancer theranostics.

Photothermal therapy (PTT) is hampered by limited light penetration depth and cell thermoresistance induced by over-expressed heat shock proteins (HSPs). Herein, we proposed a tumor-specific enhanced NIR-II PTT through the starvation mediated thermal sensitization strategy. A semiconducting polymer with superior NIR-II fluorescence imaging (FI) performance and NIR-II PTT efficacy was synthesized and encapsulated into folate modified liposomes, together with a glycolysis inhibitor, 2-deoxy-d-glucose (2DG). Upon specifically targeting folate receptors and guidance of NIR-II FI, spatiotemporal 2DG release could be achieved by the trigger of NIR-II photothermal effect. The released 2DG could not only deplete the energy supply of tumor cells by inhibiting tumor anaerobic glycolysis, but also decrease the ATP levels and hamper the production of HSPs, ultimately enhancing the tumor thermal sensitivity toward PTT. Owing to the sensitization effect of 2DG, tumor cells with overexpressed folate receptors could be significantly damaged by NIR-II PTT with an enhanced therapeutic efficiency. The work provided a promising strategy for specific starvation/NIR-II PTT synergistic therapy towards tumors.