A pulmonary codelivery system that can simultaneously deliver doxorubicin (DOX) and Bcl2 siRNA to the lungs provides a promising local treatment strategy for lung cancers. In this study, DOX is conjugated onto polyethylenimine (PEI) by using cis-aconitic anhydride (CA, a pH-sensitive linker) to obtain PEI-CA-DOX conjugates. The PEI-CA-DOX/siRNA complex nanoparticles are formed spontaneously via electrostatic interaction between cationic PEI-CA-DOX and anionic siRNA. The drug release experiment shows that DOX releases faster at acidic pH than at pH 7.4. Moreover, PEI-CA-DOX/Bcl2 siRNA complex nanoparticles show higher cytotoxicity and apoptosis induction in B16F10 cells than those treated with either DOX or Bcl2 siRNA alone. When the codelivery systems are directly sprayed into the lungs of B16F10 melanoma-bearing mice, the PEI-CA-DOX/Bcl2 siRNA complex nanoparticles exhibit enhanced antitumor efficacy compared with the single delivery of DOX or Bcl2 siRNA. Compared with systemic delivery, most drug and siRNA show a long-term retention in the lungs via pulmonary delivery, and a considerable number of the drug and siRNA accumulate in tumor tissues of lungs, but rarely in normal lung tissues. The PEI-CA-DOX/Bcl2 siRNA complex nanoparticles are promising for the treatment of metastatic lung cancer by pulmonary delivery with low side effects on the normal tissues.

A facile strategy is developed to construct an ultrasensitive pH triggered charge/size dual-rebound gene delivery system for efficient tumor treatment. The therapeutic gene is complexed by polyethylenimine (PEI) and poly-l-glutamate (PLG), further in situ tightened by aldehyde modified polyethylene glycol (PEG) via Schiff base reaction. The generated Schiff base bonds are stable in neutral pH but cleavable in tumor extracellular pH. This gene delivery system possesses following favorable properties: (1) the tunable gene delivery system is constructed by chemical bench-free “green” and fast process which is favored by clinician, (2) PEG cross-linking shields the surface positive charges and tightens the complex particles, leading to decreased cytotoxicity, improved stability, and prolonged circulation, (3) PEG shielding can be rapidly peeled off by acidic pH as soon as arriving tumors, (4) dual charge/size ultrasensitively rebounding to higher positive potential and bigger size enhances tumor cell uptake efficiency. A series of experiments both in vitro and in vivo are carried out to investigate this gene delivery system in detail. An antiangiogenesis therapeutic gene is carried for the treatment of CT26 tumors in mice, achieving superior antitumor efficacy which is well proved by sufficient biological evidence. The system has great potentials for cancer therapy in the future.

Tumor vaccine has been one of the research hotspots for cancer immunotherapy in recent years. By introducing tumor antigens into the body, the patient's own immune system will be specifically activated to induce effective immune responses for controlling or eliminating the malignant tumor cells. In this study, a simple nanovaccine was developed to induce antigen-specific anti-tumor immune responses. Polycationic polyethylenimine (PEI) was utilized to co-deliver the antigen ovalbumin (OVA) and the adjuvant unmethylated cytosine-phosphate-guanine (CpG) by electrostatic binding. The positively charged PEI could be beneficial to augment the PEI/CpG/OVA nanovaccine uptake in dendritic cells (DCs) and facilitate the endosomal escape of the nanovaccine for antigen delivering into the cytoplasm. The nanovaccine showed significant stimulation on DCs' maturation in vitro, and it was further applied for in vivo anti-tumor immunotherapy. To enhance the tumor infiltration of the nanovaccine-generated tumor-specific T cells, hyaluronidase (HAase) was employed to increase the permeability of the tumor tissues by breaking down the hyaluronan (HA) in the extracellular matrix (ECM) of tumors. Highly enhanced in vivo anti-tumor therapeutic efficiency was achieved by combining the PEI/CpG/OVA nanovaccine with HAase, which was attributed to the increased quantity of OVA-specific T cells in tumor tissues. The combination of nanovaccine with HAase has offered a simple and efficient strategy for inducing powerful anti-tumor effect in cancer immunotherapy.

Developing a comprehensive platform which has both diagnosis and therapeutic strategies is necessary for efficient tumor treatment. In this work, a Fuel Improved microRNA Explorer (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.

Low toxic theranostic nanoparticles that can simultaneously achieve effective tumor accumulation and rapid renal clearance are highly desired for imaging contrast agents and photothermal therapy (PTT) in tumor diagnosis and therapy. Herein, we report a one-pot method for preparing multifunctional nanoparticles (FeAP-NPs) based on the coordination interaction of natural polyphenols (anthocyanins) extracted from fruits, FeIII ions, and poly(l-glutamic acid)-g-methoxy poly(ethylene glycol) copolymers. The FeAP-NPs possess the following favorable advantages: (1) The components of FeAP-NPs originate from natural products, an endogenous element, and poly(amino acid) derivatives, guaranteeing their safety for in vivo application. (2) FeAP-NPs exhibit excellent dual photoacoustic (PA)/magnetic resonance (MR) imaging capacity and high photothermal efficiency. (3) FeAP-NPs can overcome the intractable dilemma of the enhanced permeability and retention (EPR) effect and renal clearance for nanomedicine through the dynamic disassembling ability, which induces a switch of the elimination pathway. Complete tumor ablation is realized by PTT in MCF-7-bearing nude mice under the precise guide of PA and MR imaging. The detailed evaluation of the safety, biodistribution, and elimination behaviors of FeAP-NPs is conducted in vitro or in vivo. This work provides a promising comprehensive solution for nanomedicine clinical application.

Intrinsically integrating precise diagnosis, effective therapy, and self-anti-inflammatory action into a single nanoparticle is attractive for tumor treatment and future clinical application, but still remains a great challenge. In this study, bovine serum albumin–iridium oxide nanoparticles (BSA-IrO2 NPs) with extraordinary photothermal conversion efficiency, good photocatalytic activity, and a high X-ray absorption coefficient were prepared through one-step biomineralization. The nanoparticles allow tumor phototherapy and simultaneous photoacoustic/thermal imaging and computed tomography. More importantly, BSA-IrO2 NPs can also act as a catalase to protect normal cells against H2O2-induced reactive oxygen pressure and inflammation while significantly enhancing photoacoustic imaging through microbubble-based inertial cavitation. These remarkable features may open up the exploration iridium-based nanomaterials in theranostics.

High transfection efficiency and low cytotoxicity are the two key factors to be considered in the design of gene carriers. Herein, a novel and versatile gene carrier (PLL-RT) was prepared by introducing “molecular string” RT (i.e., p-toluylsulfonyl arginine) onto the polylysine backbone. The introduction of RT string contributed to the formation of multiple interactions between the polycationic gene carriers and cell membrane or DNA, as well as adopting α-helix conformation, all of which would be beneficial to enhance the gene transfection. In addition, RT string grafted onto other polycations such as hyperbranced PEI25k and dendrimer PAMAM could also acquire improved transfection efficiency and low cytotoxicity. Moreover, PLL-RT presented significant tumor inhibition effect in vivo. This work provided an effective strategy for constructing novel gene carriers with high transfection and low cytotoxicity.

Despite multifunctional nanoparticles using for photothermal therapy can efficiently kill cancer cells, their further application is still hindered by the intrinsic high uptake in the reticuloendothelial system (RES) organs, causing the slow elimination from the body and potential toxicity to the body. Therefore, it is ideal to develop multifunctional nanoparticles which process the ability to effectively accumulate in tumors, while the nanoparticles can be rapidly excreted from the body via renal clearance after effective treatment. Herein, we report the multifunctional nanoparticles (FeTNPs) based on the coordination interaction of phenolic group and metal iron, which are composed of ferric iron, tannic acid (TA) and poly (glutamic acid)-graft-methoxypoly (ethylene glycol) (PLG-g-mPEG). FeTNPs exhibit the following highlighted features: (1) The effective accumulation in the tumor tissue is achieved based on EPR effect. (2) The dual photoacoustic (PA)/magnetic resonance (MR) imaging capacity can provide guidance for the photothermal therapy (PTT). (3) FeTNPs can be dynamically disassembled by deferoxamine mesylate (DFO) to accelerate elimination of the nanoparticles, thus reducing the potential toxicity for the body. The DFO triggered dynamic disassembling strategy may open a new avenue to overcome the dilemma between EPR effect and renal clearance.

Photodynamic therapy (PDT) still faces a key challenge associated with its oxygen-dependent property, which limits its therapeutic efficiency against hypoxic tumor. To address the problem, covalent organic nanosheets (CONs) are prepared with a donor–acceptor molecular heterostructure. CONs can address the hypoxic-tumor PDT by two strategies, that is, type I PDT and type I PDT combined with photothermal therapy (PTT). On the one hand, the molecular heterostructure of CONs can afford highly efficient charge carrier separation, a long lifetime of electrons and holes can be obtained, the electrons can reduce O2 to form O2·–, and at the same time, the holes can oxidize water to produce ·OH. Therefore, type I PDT is obtained, which can be used to diminish the limits of hypoxia in type II PDT. On the other hand, the recombination of photoexcited species results in an important nonradiative attenuation, and thus the energy is emitted as heat. A combination of type I PDT and PTT serves as an effective way to get around the difficulties of hypoxia in PDT. Intravenous injection of CONs in nude mice followed by the combination of type I PDT and PTT under single-wavelength irradiation achieves significant tumor ablation.

Targeted activation or enhancement is an attractive strategy in the design of nano-theranostics. However, the responsiveness of the nanoagents is restricted by the limited levels of intra-tumor stimuli. Herein, we constructed a positive feedback nanoamplifier by encapsulating glucose oxidase (GOx) in the ferric ions contained metal organic framework (MIL-100), and coating the nanoparticles with polydopamine modified hyaluronic acid (HA-PDA). The mechanism of action of the ensuing nanoamplifiers was three pronged: 1) the high intra-tumor acidity accelerated the release of GOx, which consumed endogenous glucose and “starved” the tumors, in addition to aggravating the local acidity and H2O2 levels; 2) the hydroxyl radicals (·OH) generated from the Fenton-like reaction between MIL-100 with H2O2 contributed to the chemodynamic tumor therapy and augmented the O2 microenvironment, which could be speeded up under acid condition; 3) the oxygen (O2) produced in the Fenton-like reaction relieved the intra-tumor hypoxia and ensured the enzymatic reaction of GOx, along with augmenting the photoacoustic signal of nanoamplifier. Preliminary experiments in tumor bearing mice showed that the nanoamplifier not only boosted the local acidity/H2O2/O2 levels in tumor site to successfully suppress the growth of tumors through the self-enhanced chemodynamic/starving therapy, but also achieved the photoacoustic imaging of tumors. Taken together, this novel nanoamplifier with the abilities of self-enhanced tumor imaging and therapy is a promising entrant in the field of anti-tumor theranostics.