Although smart polymer micelles able to respond to the tumor acid microenvironment are potential anticancer drug carriers, fruitful clinical application of these carriers is inadequate. For the purpose of finding the origin of the unsatisfactory therapeutic efficacy of pH-sensitive drug carriers with tertiary amine groups, we newly designed and synthesized poly­{α-[4-(diethylamino)­methyl-1,2,3-triazol]-caprolactone-co-caprolactone}-b-poly­(2-methacryloyloxyethyl phosphorylcholine) (PDCL-PMPC), a biomimetic phosphorylcholine polymer with pH-ensitive groups. PDCL-PMPC self-assembles into small and uniform micelles as its counterpart poly­(caprolactone)-b-poly­(2-methacryloyloxyethyl phosphorylcholine) (PCL-PMPC) without pH-sensitive groups. The in vitro and in vivo properties of PDCL-PMPC and PCL-PMPC micelles are investigated in detail. PDCL-PMPC micelles display obvious pH sensitivity by micelle change and fast drug release at pH 5, but the insensitive micelles do not. The internalization of PDCL-PMPC micelles by tumor cells is stronger than that of PCL-PMPC micelles. However, in comparison with the insensitive micelles, the pH-sensitive micelles present much shorter blood circulation time in pharmacokinetics and demonstrate worse accumulation in the tumor site in vivo study. As a result, DOX loaded PCL-PMPC micelles demonstrate much better antitumor efficiency than pH-sensitive micelles. Furthermore, DOX loaded PCL-PMPC micelles show similar therapeutic efficacy to DOX·HCl but with considerably lower side effects.

Hydrogels with inherent antibacterial activity and nonfouling behavior can not only provide better environment for skin wounds to avoid infection but also accelerate wound healing. Herein, 2-(methacryloyloxy) ethyl 2-(trimethylammonio) ethyl phosphate (MPC) copolymers with epoxy groups, referred to as P(MPC-co-GMA), are designed and synthesized for preparing hydrogel wound dressing with inherent antibacterial and nonfouling properties. The P(MPC-co-GMA) hydrogel network is fabricated by a ring-opening reaction of the epoxy group with nontoxic and antibacterial cystamine under mild conditions. The hydrogel shows an appropriate swelling ratio, elastic behavior, and good cytocompatibility on L929 and RBCs. Bacteria scarcely adhered on the hydrogel surfaces, and the adhered bacteria could be killed by the hydrogels. Furthermore, curcumin (Cur) could be loaded into and released from the three-dimensional network structure of the hydrogels. P(MPC-co-GMA) hydrogel and its Curloaded hydrogel can accelerate wound healing of full-thickness skin injury compared to control groups. Conclusively, this polyphosphorylcholine hydrogel displays a potential application for skin wound healing on account of inherent antibacterial activity, antibacterial adhesion behavior, and drug release ability.

Immunotherapy has emerged as a novel cancer treatment over the last decade, however, efficacious responses to mono-immunotherapy have only been achieved in a relatively small portion of patients whereas combinational immunotherapies often lead to concurrent side effects. It has been proved that the tumor microenvironment (TME) is responsible for tumor immune escape and the ultimate treatment failure. Recently, there has been remarkable progress in both the understanding of the TME and the applications of nanotechnological strategies, and reviewing the emerging immune-regulatory nanosystems may provide valuable information for specifically modulating the TME at different immune stages. In this review, we focus on comprehending the recently-proposed T-cell-based tumor classification and identifying the most promising targets for different tumor phenotypes, and then summarizing the nanotechnological strategies to best target corresponding immune-related factors. For future precise personalized immunotherapy, tailor-made TME modulation strategies conducted by well-designed nanosystems to alleviate the suppressive TME and then promote anti-tumor immune responses will significantly benefit the clinical outcomes of cancer patients.

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Combining photodynamic therapy (PDT) with natural killer (NK) cell-based immunotherapy has shown great potential against cancers, but the shedding of NK group 2, member D ligands (NKG2DLs) on tumor cells inhibited NK cell activation in the tumor microenvironment. Herein, we assembled microenvironment-/light-responsive bio-nanosystems (MLRNs) consisting of SB-3CT-containing β-cyclodextrins (β-CDs) and photosensitizer-loaded liposomes, in which SB-3CT was considered to remodel the tumor microenvironment. β-CDs and liposomes were linked by metalloproteinase 2 (MMP-2) responsive peptides, enabling sequential release of SB-3CT and chlorin e6 triggered by the MMP-2-abundant tumor microenvironment and 660 nm laser irradiation, respectively. Released SB-3CT blocked tumor immune escape by antagonizing MMP-2 and promoting the NKG2D/NKG2DL pathway, while liposomes were taken up by tumor cells for PDT. MLRNmediated photo-immunotherapy significantly induced melanoma cell cytotoxicity (83.31%), inhibited tumor growth (relative tumor proliferation rate: 1.13% of that of normal saline) in the xenografted tumor model, and enhanced tumor-infiltrating NK cell (148 times) and NKG2DL expression (9.55 and 16.52 times for MICA and ULBP-1, respectively), achieving a synergistic effect. This study not only provided a simple insight into the development of new nanomedicine for programed release of antitumor drugs and better integration of PDT and immunotherapy but also a novel modality for clinical NK cell-mediated immunotherapy against melanoma.