Light sheet fluorescence microscopy with active optical manipulation.

We present a light sheet fluorescence microscopy (LSFM) with active optical manipulation by using linear optical tweezers (LOTs). In this method, two coaxially transmitting laser beams of different wavelengths are shaped using cylindrical lenses to form a linear optical trapping perpendicular to the optical axis and an excitation light sheet (LS) parallel to the optical axis, respectively. Multiple large-sized polystyrene fluorescent microspheres are stably captured by LOTs, and their rotation angles around specific rotation axes are precisely controlled. During a sample rotation, the stationary excitation LS scans the sample to obtain fluorescence sectioning images of the sample at different angles.

Metalloporphyrin Complex-Based Nanosonosensitizers for Deep-Tissue Tumor Theranostics by Noninvasive Sonodynamic Therapy.

Metal complexes are widely used as anticancer drugs, while the severe side effects of traditional chemotherapy require new therapeutic modalities. Sonodynamic therapy (SDT) provides a significantly noninvasive ultrasound (US) treatment approach by activating sonosensitizers and initiating reactive oxygen species (ROS) to damage malignant tissues. In this work, three metal 4-methylphenylporphyrin (TTP) complexes (MnTTP, ZnTTP, and TiOTTP) are synthesized and encapsulated with human serum albumin (HSA) to form novel nanosonosensitizers. These nanosonosensitizers generate abundant singlet oxygen (1 O2 ) under US irradiation, and importantly show excellent US-activatable abilities with deep-tissue depths up to 11 cm. Compared to ZnTTP-HSA and TiOTTP-HSA, MnTTP-HSA exhibits the strongest ROS-activatable behavior due to the lowest highest occupied molecular orbital-lowest unoccupied molecular orbital gap energy by density functional theory. It is also effective for deep-tissue photoacoustic/magnetic resonance dual-modal imaging to trace the accumulation of nanoparticles in tumors. Moreover, MnTTP-HSA intriguingly achieves high SDT efficiency for simultaneously suppressing the growth of bilateral tumors away from ultrasound source in mice. This work develops a deep-tissue imaging-guided SDT strategy through well-defined metalloporphyrin nanocomplexes and paves a new way for highly efficient noninvasive SDT treatments of malignant tumors.

Surface-Functionalized Nanoparticles as Efficient Tools in Targeted Therapy of Pregnancy Complications.

Minimizing exposure of the fetus to medication and reducing adverse off-target effects in the mother are the primary challenges in developing novel drugs to treat pregnancy complications. Nanomedicine has introduced opportunities for the development of novel platforms enabling targeted delivery of drugs in pregnancy. This review sets out to discuss the advances and potential of surface-functionalized nanoparticles in the targeted therapy of pregnancy complications. We first describe the human placental anatomy, which is fundamental for developing placenta-targeted therapy, and then we review current knowledge of nanoparticle transplacental transport mechanisms. Meanwhile, recent surface-functionalized nanoparticles for targeting the uterus and placenta are examined. Indeed, surface-functionalized nanoparticles could help prevent transplacental passage and promote placental-specific drug delivery, thereby enhancing efficacy and improving safety. We have achieved promising results in targeting the placenta via placental chondroitin sulfate A (plCSA), which is exclusively expressed in the placenta, using plCSA binding peptide (plCSA-BP)-decorated nanoparticles. Others have also focused on using placenta- and uterus-enriched molecules as targets to deliver therapeutics via surface-functionalized nanoparticles. Additionally, we propose that placenta-specific exosomes and surface-modified exosomes might be potential tools in the targeted therapy of pregnancy complications. Altogether, surface-functionalized nanoparticles have great potential value as clinical tools in the targeted therapy of pregnancy complications.

ROS-Inducing Micelles Sensitize Tumor-Associated Macrophages to TLR3 Stimulation for Potent Immunotherapy.

One approach to cancer immunotherapy is the repolarization of immunosuppressive tumor-associated macrophages (TAMs) to antitumor M1 macrophages. The present study developed galactose-functionalized zinc protoporphyrin IX (ZnPP) grafted poly(l-lysine)- b-poly(ethylene glycol) polypeptide micelles (ZnPP PM) for TAM-targeted immunopotentiator delivery, which aimed at in vivo repolarization of TAMs to antitumor M1 macrophages. The outcomes revealed that ROS-inducing ZnPP PM demonstrated specificity for the in vitro and in vivo targeting of macrophages, elevated the level of ROS, and lowered STAT3 expression in BM-TAMs. Poly I:C (PIC, a TLR3 agonist)-loaded ZnPP PM (ZnPP PM/PIC) efficiently repolarized TAMs to M1 macrophages, which were reliant on ROS generation. Further, ZnPP PM/PIC substantially elevated the activated NK cells and T lymphocytes in B16-F10 melanoma tumors, which caused vigorous tumor regression. Therefore, the TAM-targeted transport of an immunologic adjuvant with ZnPP-grafted nanovectors may be a potential strategy to repolarize TAMs to M1 macrophages in situ for effective cancer immunotherapy.

Encapsulation of Hydrophilic and Hydrophobic Peptides into Hollow Mesoporous Silica Nanoparticles for Enhancement of Antitumor Immune Response.

Codelivery of combinational antigenic peptides and adjuvant to antigen presenting cells is expected to amplify tumor specific T lymphocytes immune responses while minimizing the possibility of tumor escaping and reducing immune tolerance to single antigenic peptide. However, the varied hydrophobicities of these multivariant derived short antigenic peptides limit their codelivery efficiency in conventional delivery systems. Here, a facile yet effective route is presented to generate monodisperse and stable hollow mesoporous silica nanoparticles (HMSNs) for codelivering of HGP10025-33 and TRP2180-188 , two melanoma-derived peptides with varied hydrophobicities. The HMSNs with large pore size can improve the encapsulation efficiency of both HGP100 and TRP2 after NH2 modification on the inner hollow core and COOH modification in the porous channels. HGP100 and TRP2 loaded HMSNs (HT@HMSNs) are further enveloped within monophosphoryl lipid A adjuvant entrapped lipid bilayer (HTM@HMLBs), for improved stability/biocompatibility and codelivery efficiency of multiple peptides, adjuvant, and enhanced antitumor immune responses. HTM@HMLBs increase uptake by dendritic cells (DCs) and stimulate DCs maturation efficiently, which further induce the activation of both tumor specific CD8+ and CD4+ T lymphocytes. Moreover, HTM@HMLBs can significantly inhibit tumor growth and lung metastasis in murine melanoma models with good safety profiles. HMSNs enveloped with lipid bilayers (HMLBs) are believed to be a promising platform for codelivery of multiple peptides, adjuvant, and enhancement of antitumor efficacy of conventional vaccinations.

Block Copolymer Capsules with Structure-Dependent Release Behavior.

Although high-boiling non-solvent induced macrophase separation in emulsion droplets has been widely applied for the fabrication of polymeric capsules, precise control of their structures remains a great challenge. Herein, block copolymer capsules with tunable shell structures were fabricated by employing a non-solvent as a liquid template in emulsion droplets. The properties of the non-solvents dictate the phase separation sequence in the droplets and the capsule formation mechanism. Two different pathways for capsule formation were observed, and could be applied to predict the shell structure. The structured capsules could be transformed into mesoporous capsules, which demonstrated an intriguing structure-dependent release behavior. Capsules with spherical shell structures displayed the best permeability, while those with lamellar shell structures showed the slowest release, but with a stepwise profile. After loading with an anticancer drug, different capsules induced different apoptosis ratios in cancer cell studies.

Structural Transformation of Diblock Copolymer/Homopolymer Assemblies by Tuning Cylindrical Confinement and Interfacial Interactions.

In this study, we report the controllable structural transformation of block copolymer/homopolymer binary blends in cylindrical nanopores. Polystyrene-b-poly(4-vinylpyridine)/homopolystyrene (SVP/hPS) nanorods (NRs) can be fabricated by pouring the polymers into an anodic aluminum oxide (AAO) channel and isolated by selective removal of the AAO membrane. In this two-dimensional (2D) confinement, SVP self-assembles into NRs with concentric lamellar structure, and the internal structure can be tailored with the addition of hPS. We show that the weight fraction and molecular weight of hPS and the diameter of the channels can significantly affect the internal structure of the NRs. Moreover, mesoporous materials with tunable pore shape, size, and packing style can be prepared by selective solvent swelling of the structured NRs. In addition, these NRs can transform into spherical structures through solvent-absorption annealing, triggering the conversion from 2D to 3D confinement. More importantly, the transformation dynamics can be tuned by varying the preference property of surfactant to the polymers. It is proven that the shape and internal structure of the polymer particles are dominated by the interfacial interactions governed by the surfactants.

Recent advances in targeted nanoparticles drug delivery to melanoma.

Melanoma is one of the most aggressive skin cancers, notorious for its high multidrug resistance and low survival rate. Conventional therapies (e.g., dacarbazine, interferon-alpha-2b and interleukin-2) are limited by low response rate and demonstrate no overall survival benefit. Novel targeted therapies (e.g., vemurafenib, dabrafenib and trametinib) have higher initial response rate and clear impact on the overall survival, but relapse usually occurs within 6 to 9 months. Although immunotherapy (e.g., ipilimumab, pembrolizumab and nivolumab) can achieve long-term and durable response, rate of adverse events is extremely high. With the development of nanotechnology, the applications of nanocarriers are widely expected to change the landscape of melanoma therapy for foreseeable future. In this review, we will relate recent advances in the application of multifunctional nanocarriers for targeted drug delivery to melanoma, in melanoma nanotheranostics and combination therapy, and nanopharmaceutical associated melanoma clinical trials, followed by challenges and perspectives. From the clinical editor: The team of authors describes the current treatment regimes of malignant melanoma emphasizing the importance of achieving a better efficacy and the need to develop a better understanding of melanoma tumorigenesis.

Uniform core-shell photonic crystal microbeads as microcarriers for optical encoding.

We demonstrate a rapid and robust method to fabricate uniform core-shell photonic crystal (PC) microbeads by the microfluidic and centrifugation-redispersion technique. Colored crystalline colloidal arrays (CCAs) were first prepared through centrifugation-redispersion approach by self-assembly of polystyrene-poly(N-isopropylacrylamide) (PS-PNIPAm) core/shell nanoparticles (NPs). Different from the conventional NPs (e.g., charged PS or PNIPAm NPs), PS-PNIPAm NPs could easily self-assemble into well-ordered CCAs by only one purification step without laborious pretreatment (e.g., dialysis or ion exchange) or slow solvent-evaporation process. The CCAs is then encapsulated into a transparent polymer shell with functional groups (e.g., copolymer of ETPTA and butyl acrylate (BA)), triggering the formation of core-shell PC microbeads which can be used as optical encoding microcarriers. Importantly, this technique allows us to produce core-shell PC microbeads in a rapid and robust way, and the optical reflections of the PC microbeads appear highly stable to various external stimuli (e.g., temperature, pH value, and ionic strength) relying on the features of the CCAs core and protection of the polymer shell. Moreover, various probe biomolecules (e.g., proteins, antibodies, and so on) can be easily linked on the surface of the core-shell PC microbeads owing to the hydrophilic modification induced by the hydrolysis of BA on the microbead surface, enabling the multiplex biomolecular detection.

Dynamic speckle illumination wide-field fluorescence microscopy with actively optical manipulation of rotational angles.

We present a dynamic speckle illumination wide-field fluorescence microscopy (DSIWFM) combined with a line optical tweezers (LOTs) for rotational fluorescence sectioning imaging. In this method, large polystyrene fluorescent microspheres are stably trapped with LOTs, and precisely manipulated to rotate around a specific rotation axis. During the rotation process, multiple raw fluorescence images of trapped microspheres are obtained with dynamic speckle illumination. The root-mean-square (RMS) algorithm is used to extract the drastically changing fluorescent signals in the focal plane to obtain the fluorescence sectioning images of the samples at various angles. The influence of speckle granularity on the image quality of fluorescence sectioning images is experimentally analyzed. The rotational fluorescence sectioning images obtained by DSIWFM with LOTs could provide an alternative technique for applications of biomedical imaging.

Ultra-Sensitive Detection of the SARS-CoV-2 Nucleocapsid Protein via a Clustered Regularly Interspaced Short Palindromic Repeat/Cas12a-Mediated Immunoassay.

Tracking trace protein analytes in precision diagnostics is an ongoing challenge. Here, we developed an ultrasensitive detection method for the detection of SARS-CoV-2 nucleocapsid (N) protein by combining enzyme-linked immunosorbent assay (ELISA) with the clustered regularly interspaced short palindromic repeat/CRISPR-associated protein (CRISPR/Cas) system. First, the SARS-CoV-2 N protein bound by the capture antibody adsorbed on the well plate was sequentially coupled with the primary antibody, biotinylated secondary antibody, and streptavidin (SA), followed by biotin primer binding to SA. Subsequently, rolling circle amplification was initiated to generate ssDNA strands, which were targeted by CRISPR/Cas12a to cleave the FAM-ssDNA-BHQ1 probe in trans to generate fluorescence signals. We observed a linear relationship between fluorescence intensity and the logarithm of N protein concentration ranging from 3 fg/mL to 3 × 107 fg/mL. The limit of detection (LOD) was 1 fg/mL, with approximately nine molecules in 1 µL of the sample. This detection sensitivity was 4 orders magnitude higher than that of commercially available ELISA kits (LOD: 5.7 × 104 fg/mL). This method was highly specific and sensitive and could accurately detect SARS-CoV-2 pseudovirus and clinical samples, providing a new approach for ultrasensitive immunoassay of protein biomarkers.

Shaping functional nano-objects by 3D confined supramolecular assembly.

Nano-objects are generated through 3D confined supramolecular assembly, followed by a sequential disintegration by rupturing the hydrogen bonding. The shape of the nano-objects is tunable, ranging from nano-disc, nano-cup, to nano-toroid. The nano-objects are pH-responsive. Functional materials for example inorganic or metal nanoparticles are easily complexed onto the external surface, to extend both composition and microstructure of the nano-objects.

Multiresponsive hydrogel photonic crystal microparticles with inverse-opal structure.

Hydrogel photonic crystal microparticles (HPCMs) with inverse-opal structure are generated through a combination of microfluidic and templating technique. Temperature and pH responsive HPCMs have firstly been prepared by copolymerizing functional monomers, for example, N-isopropylacrylamide (NIPAm) and methacrylic acid (MAA). HPCMs not only show tunable color variation almost covering the entire wavelength of visible light (above 150 nm of stop-band shift) by simply tailoring temperature or pH value of the solution, but also display rapid response (less than 1 min) due to the small volume and well-ordered porous structure. Importantly, the temperature sensing window of the HPCMs can be enlarged by controlling the transition temperature of the hydrogel matrix, and the HPCMs also exhibit good reversibility and reproducibility for pH response. Moreover, functional species or particles (such as azobenzene derivative or magnetic nanoparticles) can be further introduced into the hydrogel matrix by using post-treatment process. These functionalized HPCMs can respond to the UV/visible light without significantly influencing the temperature and pH response, and thus, multiresponsive capability within one single particle can be realized. The presence of magnetic nanoparticles may facilitate secondary assembly, which has potential applications in advanced optical devices.

Multifunctional biodegradable polymer nanoparticles with uniform sizes: generation and in vitro anti-melanoma activity.

We present a simple, yet versatile strategy for the fabrication of uniform biodegradable polymer nanoparticles (NPs) with controllable sizes by a hand-driven membrane-extrusion emulsification approach. The size and size distribution of the NPs can be easily tuned by varying the experimental parameters, including initial polymer concentration, surfactant concentration, number of extrusion passes, membrane pore size, and polymer molecular weight. Moreover, hydrophobic drugs (e.g., paclitaxel (PTX)) and inorganic NPs (e.g., quantum dots (QDs) and magnetic NPs (MNPs)) can be effectively and simultaneously encapsulated into the polymer NPs to form the multifunctional hybrid NPs through this facile route. These PTX-loaded NPs exhibit high encapsulation efficiency and drug loading density as well as excellent drug sustained release performance. As a proof of concept, the A875 cell (melanoma cell line) experiment in vitro, including cellular uptake analysis by fluorescence microscope, cytotoxicity analysis of NPs, and magnetic resonance imaging (MRI) studies, indicates that the PTX-loaded hybrid NPs produced by this technique could be potentially applied as a multifunctional delivery system for drug delivery, bio-imaging, and tumor therapy, including malignant melanoma therapy.

Biomimetic Nanosonosensitizers Combined with Noninvasive Ultrasound Actuation to Reverse Drug Resistance and Sonodynamic-Enhanced Chemotherapy against Orthotopic Glioblastoma.

Glioblastoma (GBM) is the most devastating brain tumor and highly resistant to conventional chemotherapy. Herein, we introduce biomimetic nanosonosensitizer systems (MDNPs) combined with noninvasive ultrasound (US) actuation for orthotopic GBM-targeted delivery and sonodynamic-enhanced chemotherapy. MDNPs were fabricated with biodegradable and pH-sensitive polyglutamic acid (PGA) and the chemotherapeutic agent and sonosensitizer doxorubicin (DOX), camouflaged with human GBM U87 cell membranes. MDNPs presented homologous targeting accumulation and in vivo long-term circulation ability. They effectively passed through the blood-brain barrier (BBB) under US assistance and reached the orthotopic GBM site. MDNPs exhibited controllable US-elicited sonodynamic effect by generation of reactive oxygen species (ROS). ROS not only induced cancer cell apoptosis but also downregulated drug-resistance-related factors to disrupt chemoresistance and increase sensitivity to chemotherapy. The in vivo study of orthotopic GBM treatments further proved that MDNPs exhibited US-augmented synergistic antitumor efficacy and strongly prolonged the survival rate of mice. The use of low-dose DOX and the safety of US enabled repeated treatment (4 times) without obvious cardiotoxicity. This effective and safe US-enhanced chemotherapy strategy with the advantages of noninvasive brain delivery and high drug sensitivity holds great promise for deep-seated and drug-resistant tumors.

A Dual-Biomineralized Yeast Micro-/Nanorobot with Self-Driving Penetration for Gastritis Therapy and Motility Recovery.

Micro-/nanorobots have attracted great interest in the field of drug delivery and treatment, while preparations for biocompatible robots are extremely challenging. Here, a self-driving yeast micro-/nanorobot (Cur@CaY-robot) is designed via dual biomineralization and acid catalysis of calcium carbonate (CaCO3). Inner nano-CaCO3 inside yeast cells (CaY) is biomineralized through cell respiration and provides nanoscaffolds for highly encapsulating curcumin (Cur). Meanwhile, the CaCO3 crystals outside yeast cells (outer-CaCO3) through uniaxial growth offer an asymmetric power source for self-propelled motility. The Cur@CaY-robot displays an efficient motion in gastric acid, with the potential for deep penetration to the thick gastric mucus, which significantly improves the accumulation of drug agents in the stomach wall tissue for robust gastritis therapy. More importantly, Ca2+ cations released from the Cur@CaY-robot also synergistically repair the gastric motility of gastritis mice. Such yeast micro-/nanorobots exhibit desirable biocompatibility and biodegradability with a good loading capacity for drugs. This work provides an idea for the design of micro-/nanorobots through an environmentally friendly biosynthesis strategy for active drug delivery and precise therapy.

A mitochondria-targeting self-assembled carrier-free lonidamine nanodrug for redox-activated drug release to enhance cancer chemotherapy.

Mitochondria play a vital role in maintaining cellular homeostasis. In recent years, studies have found that mitochondria have an important role in the occurrence and development of tumors, and targeting mitochondria has become a new strategy for tumor treatment. Lonidamine (LND), as a hexokinase inhibitor, can block the energy supply and destroy mitochondria. However, poor water solubility and low mitochondrial selectivity limit its clinical application. To overcome these obstacles, we report redox-activated self-assembled carrier-free nanoparticles (Cy-TK-LND NPs) based on a small molecule prodrug, in which photosensitizer IR780 (Cy) which targets mitochondria is conjugated to LND via a sensitive thioketal (TK) linker. Intracellular oxidative stress induced by laser radiation leads to the responsive cleavage of Cy-TK-LND NPs, facilitating the release of free LND into mitochondria. Subsequently, LND damages mitochondria, triggering the apoptosis pathway. The results show the effective killing effect of Cy-TK-LND NPs on cancer cells in vitro and in vivo. The IC50 value of irradiated Cy-TK-LND NPs is 5-fold lower than that of free LND. Moreover, tumor tissue section staining results demonstrate that irradiated Cy-TK-LND NPs induce necrosis and apoptosis of tumor cells, upregulate cytochrome C and pro-apoptotic Bax, and downregulate anti-apoptotic Bcl-2. Generally, Cy-TK-LND NPs exhibit efficient mitochondria-targeted delivery to improve the medicinal availability of LND. Accordingly, such a carrier-free prodrug-based nanomedicine holds promise as an effective cancer chemotherapy strategy.

Photosensitizer-loaded gold nanocages for immunogenic phototherapy of aggressive melanoma.

Malignant melanoma remains the life-threatening form of skin cancer with high mortality and poor prognosis. Thus, an ideal melanoma therapeutic strategy is of immediate importance which can remove the primary tumor, as well as inhibit the metastasis and recurrence. Here, we report the fabrication of adjuvant monophosphoryl lipid A (MPLA) lipid bilayer-enveloped and photosensitizer indocyanine green (ICG)-loaded gold nanocages (MLI-AuNCs) for immunogenic phototherapy of aggressive melanoma. Hollow porous AuNCs are used as carriers to deliver MPLA and ICG, and protect ICG from photodegradation. Both AuNCs and ICG absorb near infrared (NIR) light and can be applied in controllable NIR-triggered photothermal and photodynamic combination therapy (PTT/PDT) of melanoma. MLI-AuNCs coated by thermosensitive lipid bilayer exhibit uniform size, good biocompatibility and bioavailability with prominent tumor accumulation, which further improve the PTT/PDT efficacy. MLI-AuNCs under NIR irradiation not only destroy the primary tumor by PTT/PDT, but also elicit robust antitumor immune response with melanoma associated antigens and MPLA released in situ. The released antigens and MPLA subsequently enhance the recruitment and maturation of dendritic cells, which further activate the effector T cells to inhibit metastases and recurrence of melanoma. This immunomodulatory-boosted PTT/PDT nanoplatform provides a new opportunity for highly aggressive melanoma treatment. STATEMENT OF SIGNIFICANCE: An ideal tumor therapeutic strategy not only can remove the primary tumor, but also inhibit metastasis and recurrence. Here, we introduced a versatile nanoplatform MLI-AuNCs for immunogenic phototherapy of aggressive melanoma. Adjuvant MPLA and photosensitizer ICG can be protected and co-delivered to the tumors by thermosensitive lipid-enveloped AuNCs. MLI-AuNCs exhibited prominent tumor accumulation ability and produced the potent PTT/PDT effect to destroy the primary tumors with a single dose of NIR irradiation, as well as elicited the strong antitumor immunity to inhibit the metastasis and relapse. This study may provide a potential therapeutic vaccination strategy against advanced melanoma and other difficult-to-treat cancers.

Biodegradable polymer microcapsules fabrication through a template-free approach.

A detailed study on the direct synthesis of biocompatible polyesters (e.g., PLA, PLGA or PCL) microcapsules and multifunctional microcapsules, which does not require any template and core removal, is presented. The technique is based on the modified self-emulsification process within the emulsion droplets by simply adding sodium dioctyl sulfosuccinate (Aerosol OT or AOT) as a cosurfactant to the initial polymer solution, followed by double emulsion formation due to the coalescence of the internal water droplets. Microcapsules with tunable sizes (ranging from hundreds of nanometers to tens of micrometers) and morphologies were then obtained through solidification of droplet shell of the double emulsion via solvent removal. In this report, we have systematically investigated the effect of experimental parameters, such as polymer and AOT concentration, polymer molecular weight on the double emulsion formation process, and the final morphologies of the microcapsules. We demonstrate that the capsules can encapsulate either hydrophobic or hydrophilic dyes during solvent evaporation. Dye-release studies show a correlation between shell thickness, capsules size, and diffusive release rate, providing insights into the shell formation and shell thickness processing. Moreover, hydrophobic nanoparticles, such as oleic-acid coated Fe(3)O(4) nanoparticles and quantum dots, can also be incorporated into the walls of the microcapsules. Such functional microcapsules might find applications in the fields of controlled release, bioimaging, diagnostics, and targeting.

In situ poly I:C released from living cell drug nanocarriers for macrophage-mediated antitumor immunotherapy.

Immunotherapy is one of the most promising approaches to inhibit tumor growth and metastasis by activating host immune functions. However, the arising problems such as low immune response caused by complex tumor microenvironment and extremely systemic immune storm still limit the clinical applications of immunotherapy. Here, we construct Poly I: C-encapsulated poly (lactic-co-glycolic acid) nanoparticles (PLP NPs) with a slow release profile. A biomimetic system (MPLP), which loads PLP NPs on the surface of bone marrow-derived macrophage (BMDM) via the maleimide-thiol conjugation, is synthesized to effectively deliver PLP, control drug release and activate the tumor-specific immune response in situ. The results show that PLP NPs loading does not affect the activity and function of BMDM. Then, BMDM acts as a living cell drug vehicle and promotes the accumulation of PLP NPs in tumors, where Poly I: C is released from PLP NPs and reprograms BMDM into tumoricidal M1 macrophage. Furthermore, MPLP triggers potent antitumor immune responses in vivo and effectively inhibits local and metastatic tumors without causing adverse pathological immune reactions. This study offers an inspiration to facilitate clinical translation through the delivery of drugs by living immune cells for future anticancer therapy.