Effective combination therapy requires targeted co-delivery of multiple therapeutic agents via a well-defined and controllable assembly mechanism, which most reported strategies struggle to achieve. In this study, we designed a tumor acidity-driven transformable nanoparticle self-assembly using a drug-conjugated amphiphilic polymer (mPEG-PLA-Ce6), an acidity-sensitive polymer (PAEMA), and the CSF-1R inhibitor, sotuletinib (BLZ-945), by regulating the pKa and ratio of the acidity-sensitive material (denoted as Ce6SNP/B). The obtained tumor acidity-driven transformable Ce6SNP/B released BLZ-945 to deplete immunosuppressive M2-type tumor-associated macrophages predominantly localized in the perivascular regions of blood vessels. Simultaneously, tumor acidity-driven size shrinkage of Ce6SNP/B facilitated the deep penetration and tumor accumulation of photosensitizer Ce6 to enhance phototherapy, resulting in enhanced immunogenic cell death of tumor cells. Additionally, the acidity-sensitive material PAEMA has the potential to induce dendritic cell maturation. Thereby, the tumor acidity-driven transformable Ce6SNP/B achieved cancer photoimmunotherapy by targeting tumor cells and activating antigen-presenting cell-mediated anti-tumor immune effect.

Local delivery systems bypass multiple delivery barriers and enhance the therapeutic agent concentration at the desired site via direct injection or post-operative implantation; however, their inability to refill therapeutic agents significantly limits their therapeutic efficacy. To address this issue, a refillable nanodrug-capturing system comprising a β-cyclodextrin (βCD)-modified alginate hydrogel (CdGel) and adamantane (Ad)-decorated nanoparticles (AdNPs) is developed herein. CdGel, locally administered at the disease site, captures and retains systemically injected drug-loaded AdNPs through host-guest interactions, enabling therapeutic agent refilling at the target site. Through the repetitive systemic administration of AdNPs, the refilling capacity of CdGel significantly enhances the anti-metastatic activity of the extracellular-targeted drug batimastat in both orthotopic and post-operative 4T1 breast tumor models. The proposed system facilitates the sequential administration of various drugs for combined cancer therapy and integrates the advantages of local and systemic delivery systems, enabling the enhanced drug accumulation and retention at the desired site.

The mechanical properties of nanoparticles play a critical role in regulating their biological fate for drug delivery. This review analyzes the impact of nanoparticle elasticity on typical drug transport processes that have been explored in the past few decades, including blood circulation, tissue and tumor targeting, tumor penetration, cellular internalization, and drug release. Moreover, the relative mechanism is analyzed and discussed. This review provides useful clues for the design of new nanoparticles and better strategies for enhancing drug delivery and antitumor efficacy.

Ribonucleic acids (RNAs) enable disease-related gene inhibition, expression, and editing and represent promising therapeutics in various diseases. The efficacy of RNA relies heavily on the presence of a secure and effective delivery system. Herein, we found that RNA could be hydrophobized by cationic lipid and ionizable lipid and conveniently coassemble with amphiphilic polymer to achieve micelle-like nanoparticles (MNP). The results of the study indicate that MNP exhibits a high level of efficiency in delivering RNA. Besides, the MNP encapsulating siRNA that targets CD47 and PD-L1 remarkably blocked these immune checkpoints in a melanoma tumor model and elicited a robust immune response. Moreover, the MNP encapsulating the mRNA of OVA achieved antigen translation and presentation, leading to an effective antitumor immunoprophylaxis outcome against OVA-expressing melanoma model. Our findings suggest that RNA hydrophobization could serve as a viable approach for delivering RNA, thereby facilitating the exploration of RNA therapy in disease treatment.

Metal-ion therapy is an emerging technique for cancer treatment, where anticancer metals trigger an immune response against tumor cells due to immunogenic cell death while enabling chemokinetic therapy, and the integration of these activities holds considerable anticancer potential for achieving high specificity and efficiency. Herein, we designed acid-responsive manganese-based nanogels with high drug-loading capacity for combined chemotherapy, chemodynamic therapy, and metal-immune therapy. The chemotherapeutic drug mitoxantrone, metallic manganese ions, and polymeric polyacrylic acid self-assembled into stable nanogels that could be efficiently internalized by cancer cells efficiently, releasing Mn2+ to catalyze highly toxic of hydroxyl generation from endogenous H2O2 and induce tumor cell apoptosis. Furthermore, the Mn2+-mediated activation of cyclic guanosine monophosphate adenosine synthetase activated the stimulator of interferon genes (STING) pathway, thereby inducing dendritic cell maturation. Following intravenous injection into immunocompetent tumor-bearing mice, the nanogels effectively exerted a tumor-killing effect and enhanced the antitumor immune response in combination with an aCTLA-4 antibody. Manganese ions also enhanced T1-weighted magnetic resonance imaging for integrated diagnosis and treatment. Overall, the manganese-based nanogel demonstrates significant synergistic efficacy through combined chemotherapy, chemodynamic therapy and metal-immune therapy, providing a versatile therapeutic strategy for cancer treatment.

Low immune infiltration severely hinders the efficacy of cancer immunotherapy. Here, we developed a manganese-phenolic network platform (TMPD) to boost antitumor immunity via a stimulator of interferon gene (STING)-amplified activation cascade. TMPD is based on doxorubicin (DOX)-loaded PEG-PLGA nanoparticles and further coated with manganese (Mn2+)-tannic acid (TA) networks. Mechanistically, DOX-based chemotherapy and Mn2+-mediated chemodynamic therapy effectively promoted immunogenic cell death (ICD), characterized by abundant damage-associated molecular pattern (DAMP) exposure, which subsequently enhanced dendritic cells' (DCs) presentation of antigens. DOX-elicited DNA damage simultaneously caused cytoplasmic leakage of intracellular double-stranded DNA (dsDNA) as the STING signal initiator, while Mn2+ mediated significant upregulation in the expression of a STING pathway-related protein thereby amplifying the STING signal. Systemic intravenous administration of TMPD remarkably promoted DC maturation and CD8(+) T cell infiltration, thus eliciting strong antitumor effects. Meanwhile, the released Mn2+ could serve as a contrast agent for tumor-specific T-1-weighted magnetic resonance imaging (MRI). Moreover, TMPD combined with immune checkpoint blockade (ICB) immunotherapy significantly inhibited tumor growth and lung metastasis. Collectively, these findings indicate that TMPD has great potential in activating robust innate and adaptive immunity for MRI guided cancer chemo-/chemodynamic/immune therapy.

In situ tumor vaccination has aroused tremendous interest with its capability for eliciting strong and systemic antitumor immune responses. Unlike traditional cancer vaccines, in situ tumor vaccination avoids the laborious process of tumor antigen identification and can modulate tumor immunosuppressive microenvironment at the same time. In recent years, bacteria have been used as both efficient tumor-targeted delivery vehicles and potent adjuvants. Regarding the rapid development in this area, in this review, we summarize recent advances in the application of bacteria for in situ cancer vaccination. We illustrate the mechanisms of bacteria as both efficient tumor immunogenic cell death inducers and tumor-targeted delivery platforms. Then we comprehensively review the engineering strategies for designing bacteria-based in situ vaccination, including chemical modification, nanotechnology, and genetic engineering. The current dilemma and future directions are discussed at the end of this review.

Photodynamic therapy (PDT), as a non-invasive and spatiotemporally controllable modality, exhibits great potential in cancer treatment. However, the efficiency of reactive oxygen species (ROS) production was restricted to the hydrophobic characteristics and aggregation-caused quenching (ACQ) of photosensitizers. Herein, we designed a ROS self-activatable nano system (denoted as PTKPa) based on poly(thioketal) conjugated with photosensitizers (PSs) pheophorbide A (Ppa) on the polymer side chains for suppressing ACQ and enhancing PDT. The process of self-activation is that ROS, which is derived from laser irradiated PTKPa, as an activating agent accelerates poly(thioketal) cleavage with the release of Ppa from PTKPa. This in turn generates abundant ROS, accelerates degradation of the remaining PTKPa and amplifies the efficacy of PDT with more tremendous ROS generated. Moreover, these abundant ROS can amplify PDT-induced oxidative stress, cause irreversible damage to tumor cells and achieve immunogenic cell death (ICD), thereby boosting the efficacy of photodynamic-immunotherapy. These findings provide new insights into ROS self-activatable strategy for enhancing cancer photodynamic- immunotherapy. STATEMENT OF SIGNIFICANCE: This work described an approach to utilize ROS-responsive self-activatable poly(thioketal) conjugated with pheophorbide A (Ppa) for suppressing aggregation-caused quenching (ACQ) and enhancing photodynamic-immunotherapy. The ROS, generated from the conjugated Ppa upon 660nm laser irradiation, as a triggering agent which initiates the release of Ppa with poly(thioketal) degradation. That in turn generates abundant ROS and facilitates degradation of the remaining PTKPa, resulting in oxidative stress to tumor cells and achieving immunogenic cell death (ICD). This work provides a promising solution to improve tumor photodynamic therapeutic effects.

Metastatic triple-negative breast cancer (TNBC) has a poor prognosis and high mortality with no effective treatment options, and immunotherapy is highly anticipated as a potential treatment but is limited by the lack of tumor-infiltrating T lymphocytes in TNBC. Herein, red blood cell (RBC) membrane-camouflaged polyphosphoester (PPE) nanoparticles (RBC@PPEMTO/PFA) are prepared as the nanocarriers of mitoxantrone (MTO) and perfluoroalkane (PFA) for synergized immunotherapy. The encapsulated MTO can generate heat and reactive oxygen species (ROS) to achieve photothermal and photodynamic therapy; moreover, ROS further triggers the self-accelerating release of MTO from the ROS-sensitive PPE core to enable chemotherapy. The RBC@PPEMTO/PFA-mediated sequential photothermal/photodynamic/chemotherapy efficiently promotes the infiltration of CD8(+) T cells into TNBC tumor tissue and synergizes the therapeutic activity of an immune checkpoint blockade antibody for metastatic TNBC treatment in distant and lung metastasis models. This biomimetic nanomedicine of MTO provides a convenient and available strategy to sensitize TNBC to immune checkpoint blockade antibody.

Tumor associated macrophages（TAMs）is one of the most abundant immune cells in the tumor microenvironment.M2-TAMs play an important role in tumor genesis,progression,metastasis and treatment,and is additionally a very important target in tumor therapy.Previous studies have shown that inhibition of tumor growth and metastasis can be achieved by reprogramming M2-TAMs to M1-TAMs.On the basis,this review focuses on the analysis progress of nano-drug reprogramming TAMs to boost anti-tumor.In this paper,we reviewed two methods of reprogramming TAMs for targeted delivery of various active substances and indirect reprogramming TAMs for abnormal tumor microenvironment regulation mediated by nanomedicine.The regulatory strategies and typical samples of nanomedicine delivery systems in recent years were summarized.

Multifunctional magnet-fluorescent nanocomposites are widely applied in biomedical applications. Incorporating biocompatible quantum dots with highly ferrimagnetic magnetic nanoparticles into one nanoplatform for achieving efficient magnetic hyperthermia therapy (MHT) is very important. Herein, we reported an amphiphilic block copolymer with a flowable hydrophobic chain to encapsulate highly ferrimagnetic magnetic nanoparticles and ZnS/InP quantum dots via a facile self-assembly method. The obtained ferrimagnetic fluorescent micelle (FMFM) exhibited a uniform diameter of about 180 nm. In stark contrast, larger aggregation (400 nm in diameter) inevitably occurred using common poly(D,L-lactide) (PLA)-based amphiphilic block copolymer with a rigid hydrophobic chain, which was readily cleared by the reticuloendothelial system (RES). The flowable FMFM exhibited long-term colloidal stability within one month and desired fluorescent stability within 84 h. Benefiting from the high ferrimagnetism, the FMFM revealed excellent magnetic heating effect and magnetic resonance imaging capability. With accurate manipulation under an external magnetic field, FMFM realized in vitro enhanced fluorescence imaging sensitivity and accumulation efficiency at the tumor region, achieving in vitro and vivo improved MHT efficacy.

In recent years, directly damaging cell membrane therapeutic modalities have attracted great attention in the field of cancer therapy due to their critical role in guaranteeing essential cellular function. In this study, the transformable nanoassembly PEG-Ce6@PAEMA, consisting of the photosensitizer polyethylene glycol-chlorin-e6 (PEG-Ce6) and tumor pH-sensitive polymer poly(2-azepane ethyl methacrylate) (PAEMA), was developed for highly efficient membrane-targeted photodynamic therapy. The PAEMA core is rapidly protonated at the acidic tumor pH, resulting in the disassembly of PEG-Ce6@PAEMA and regeneration of PEG-Ce6. Subsequently, the resultant PEG-Ce6 with a very small size (~2.6 kDa) ensures deep penetration into tumor tissue and direct and rapid anchoring to the cancer cell membrane, eventually achieving superior tumor growth inhibition under light irradiation. Thus, this tumor acidity-driven transformable polymeric nanoassembly provides a simple but efficient strategy for membrane targeting cancer therapy.

Simultaneously targeting tumor cells and nonmalignant cells represent a more efficient strategy for replacing the traditional method of targeting only tumor cells, and co-delivery nanocarriers have inherent advantages to achieve this goal. However, differential delivery of multiple agents to various types of cell with different spatial distribution patterns remains a large challenge. Herein, we developed a nanocarrier of platinum(IV) prodrug and BLZ-945, BLZ@S-NP/Pt, to differentially target tumor cells and tumor-associated macrophages (TAMs). The BLZ@S-NP/Pt undergoes shrinkage to small platinum(IV) prodrug-conjugating nanoparticles under 660 nm light, resulting in deep tumor penetration to kill more cancer cells. Meanwhile, such shrinkage also enables the rapid release of BLZ-945 in the perivascular regions of tumor to preferentially deplete TAMs (enriched in perivascular regions). Therefore, BLZ@S-NP/Pt differentially and precisely delivers agents to TAMs and tumor cells located in different spatial distribution, respectively, eventually having synergistic anticancer effects in multiple tumor models.

Reactive oxygen species (ROS)-responsive nanocarriers have aroused widespread interest in recent years. On the one hand, a high ROS level has been detected in many types of tumor cells. On the other hand, ROS generation is also induced during photodynamic, sonodynamic, or chemodynamic therapy. In addition, multiple types of polymers are sensitive to ROS. Therefore, numerous ROS-responsive polymeric nanocarriers with unique ROS-responsive characteristics have been developed. This review discusses ROSsensitive polymeric nanocarriers to improve drug delivery efficacy. In particular, ROS-responsive nanocarriers for synergistic cancer therapy are highlighted. The development of novel ROS-sensitive nanocarriers holds great potential for combining ROS-mediated therapy, such as photodynamic therapy, and other therapies to achieve synergistic anticancer efficacy. Statement of significance Reactive oxygen species (ROS)-responsive nanocarriers aroused widespread interest in recent years. On the one hand, a high level of ROS has been found in many types of tumor cells. On the other hand, the ROS generation can also be induced during the photodynamic, sonodynamic, or chemodynamic therapy. Besides, multiple types of polymers were sensitive to the ROS. Therefore, numerous ROS-responsive polymeric nanocarriers with unique ROS responsive characteristics have been developed. This review focuses on the ROS-sensitive polymeric nanocarriers to improve drug delivery efficacy for synergistic cancer therapy. (c) 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

In a recent publication [1], these images in Figures 6(b, c) (NPEG-NPCe6 group), S7, S9 and S10 were inadvertently taken the incorrect images in the production. The corrected versions are shown below. And, the quantification of Ce6 fluorescence (as performed in Figure 6(c)) was also corrected (Figure S12).

The cell nucleus-targeted delivery of therapeutic agents plays a critical role in cancer therapy, since the biological target of many anticancer therapeutics is the cell nucleus. However, multiple physiological barriers limit the delivery efficiency of free drugs, resulting in unsatisfactory therapeutic effects. Herein, thioketal crosslinked polyphosphoester-based nanoparticles with a tumor acidity (pH(e))-sensitive transactivator of transcription (TAT) peptide (DA-masked TAT-decorating reactive oxygen species (ROS)-sensitive Ce6/DOX-loaded hyperbranched nanoparticles ((TRCD)-T-D)) are explored for cascade nucleus-targeted drug delivery. Following administration, (TRCD)-T-D experiences prolonged circulation by masking the targeting effect of its TAT peptide and then achieves enhanced tumor cell uptake and improved translocation into the perinuclear region by reactivating the TAT targeting capability in tumor tissue. Subsequently, ROS generated by (TRCD)-T-D under 660 nm laser not only disrupts the nuclear membrane to allow entry into the nuclei but also triggers intracellular release of the payload in the nuclei. As evidenced by in vivo experiments, such pH(e)/photo dual-sensitive polymeric nanocarriers offer remarkable therapeutic effects, efficiently suppressing tumor growth. This multistage cascade nucleus-targeted drug delivery concept provides new avenues to develop nucleus-targeted drug delivery systems.

Checkpoint inhibitors, such as anti-PD-1/PD-L1 antibodies, have been proven as a promising type of immunotherapy in a number of cancers, but the relatively low response rates limit their scope of clinical application. Here, we report the use of cascade chemo-photodynamic therapy (chemo-PDT) with reactive oxygen species (ROS)-sensitive lipid-polymer hybrid nanoparticles TKHNP-C/D to potentiate the antitumor efficacy of anti-PD-L1 antibody (aPD-L1). Under light irradiation, TKHNP-C/D not only induced photodynamic therapy (PDT) but also boosted intracellular DOX release via the rapid degradation of its hydrophobic core, promoting an efficient cascade of chemo-PDT to inhibit tumor growth by a single treatment. More importantly, the cascade chemo-PDT could evoke anticancer immune responses and efficiently synergize with aPD-L1 to generate an abscopal effect, which could simultaneously inhibit primary and distant tumor growth.

Rationale: PEGylation of nanocarriers could extend blood circulation time and enhance tumor accumulation via the enhanced permeability and retention (EPR) effect. Unfortunately, the PEG moiety suppresses tumor cell internalization of nanocarriers, resulting in limited therapeutic efficiency (known as the PEG dilemma). Designing stimuli-responsive shell-detachable nanocarriers, which could detach the PEG corona from the nanocarriers in desired tumor tissues in response to the local environment, is an appealing approach to overcome the PEG dilemma, but nanocarrier applications are also limited by a lack of universal stimuli for PEG detachment. Methods: In this study, we synthesized red light-responsive, amphiphilic mPEG bridged to the photosensitizer Ce6 via a thioketal (TK) bond (mPEG-TK-Ce6), which was then used to achieve the PEGylation of polylactide (PLA)-based nanoparticles encapsulating the Pt(IV) prodrug. The therapeutic efficacy of the prepared nanoparticles was evaluated in vitro and in vivo. Results: We demonstrated that the amphiphilic mPEG-TK-Ce6 can realize the PEGylation of Pt(IV) prodrug-loaded PLA nanoparticles and consequently enhanced nanoparticle accumulation in tumor tissues. When the tumor tissues were subjected to 660 nm irradiation, reactive oxygen species (ROS) generated by Ce6 induced the rapid degradation of the adjacent TK bond, resulting in PEG detachment and enhanced tumor cell internalization. Therefore, mPEG-TK-Ce6 facilely achieved PEGylation and light-responsive dePEGylation of the nanocarrier for enhanced antitumor efficacy in nanomedicine. Conclusion: Such red light-responsive amphiphilic mPEG-TK-Ce6 facilely achieved PEGylation and dePEGylation of the nanocarrier, providing a facile strategy to overcome PEG dilemma.

The extremely inefficient endosomal escape and intracellular release are the central barriers for effective nanocarrier-mediated RNA interference (RNAi) therapeutics. Accelerating endosomal escape and triggering intracellular release with red or near-infrared light are of particular interest due to its spatiotemporal controllability, great tissue penetration, and minimal phototoxicity. As a proof-of-concept, we explored an innovative siRNA delivery system, TKPEI-Ce6, that is prepared by the linking reaction of branched polyethylenimine, a reactive oxygen species (ROS)-labile crosslinker, poly(ethylene glycol), and chlorin e6 (Ce6). TKPEI-Ce6 efficiently condensed siRNA to form the nanoscale complex TKPEI-Ce6/siRNA. Under red-light irradiation (660 nm), the conjugated Ce6 produced ROS, which could accelerate endosomal escape by the destruction of the endosomal membranes and then trigger the cytosolic release of siRNA by cleaving the thioketal linker and further disrupting the nanostructure of the TKPEI-Ce6/siRNA. Therefore, the superior silencing efficiency of siRNA was collectively realized toward an anticancer therapy. This concept also provides new avenues for light-controlled site-specific downregulation of targeted gene expression in vivo, facilitating precise treatment of numerous diseases.

Near-infrared (NIR) light-induced photothermal therapy (PTT) has attracted much interest in recent years. In the NIR region, tissue penetration ability of the second biological near-infrared window (1000 -1350 nm) is recognized to be stronger than that of the first window (650-950 nm). However, NIR light absorbers in the second NIR region (NIR-II) have been scant even though various NIR light absorbers in the first NIR region (NIR-I) have been widely explored. In this work, a thieno-isoindigo derivative-based semiconducting polymer, PBTPBF-BT, were formulated into PEGylated nanoparticles. The obtained nanoparticle NPPBTPBF-BT exhibited strong absorption in NIR-II region, inherent high photothermal conversion efficacy, and excellent photostability. The in vitro and in vivo PTT study employing 1064 nm laser in NIR-II window revealed that NPPBTPBF-BT could efficiently ablate tumor cell at a power density of 0.42 W/cm(2) (the skin tolerance threshold value). Moreover, NPPBTPBF-BT with excellent photostability exhibited enhanced photoacoustic (PA) imaging of tumor in living mice, suggesting the great probability of using NPPBTPBF-BT for in vivo PA imaging-guided FIT in the NIR-II window. (C) 2017 Elsevier Ltd. All rights reserved.