Extensive recent progress has been made on the design and applications of organic photothermal agents for biomedical applications because of their excellent biocompatibility comparing with inorganic materials. One major hurdle for the further development and applications of organic photothermal agents is the rarity of high‐performance materials in the second near‐infrared (NIR‐II) window, which allows deep tissue penetration and causes minimized side effects. Up till now, there have been few reported NIR‐II‐active photothermal agents and their photothermal conversion efficiencies are relatively low. Herein, optical absorption of π‐conjugated small molecules from the first NIR window to the NIR‐II window is precisely regulated by molecular surgery of substituting an individual atom. With this technique, the first demonstration of a conjugated oligomer (IR‐SS) with an absorption peak beyond 1000 nm is presented, and its nanoparticle achieves a record‐high photothermal conversion efficiency of 77% under 1064 nm excitation. The nanoparticles show a good photoacoustic response, photothermal therapeutic efficacy, and biocompatibility in vitro and in vivo. This work develops a strategy to boost the light‐harvesting efficiency in the NIR‐II window for cancer theranostics, offering an important step forward in advancing the design and application of NIR‐II photothermal agents.

Aberrant mechanical properties and immunosuppression are the two key factors that limit the antitumor efficacy of T cell immune checkpoint blockade inhibitors, e.g., programmed cell death‐1 antibody (PD‐1 Ab), against solid tumors in the clinic. This study leverages hyperbaric oxygen (HBO) for the first time to address these two issues and reports the PD‐1‐Ab‐mediated immune responses against various stroma‐rich solid malignancies. The results demonstrate that HBO promoted PD‐1 Ab delivery and T cells infiltration into tumor parenchyma by depleting the extracellular matrix's main components, such as collagen and fibronectin. Furthermore, HBO disrupts hypoxia‐mediated immunosuppression and helps PD‐1 Ab trigger robust cytotoxic T lymphocytes and long‐lasting immunological memory to inhibit tumor relapses. Such enhanced immune responses are effective in solid tumors from rodents and the cancer cells from hepatocellular carcinoma patients. The results illustrate that HBO bolsters antitumor efficacy of PD‐1 Ab, and the HBO–PD‐1 Ab combination is a promising stroma‐rich solid tumors’ treatment in the clinic.

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Metrics & MoreArticle Recommendations CONSPECTUS: Cancer stem cells (CSCs), also known as tumor initiating cells or tumor repopulating cells, which comprise only a small fraction of tumor, have received tremendous attention during the past two decades, as they are considered as the ringleader for initiation and progression of tumors, therapy resistance, metastasis, and recurrence in the clinic. Hence, eradicating CSCs is critical for successful cancer treatment. To that end, various CSC-targeting therapeutic agents have been pursued. However, these CSC-specific drugs are ineffective toward bulk cancer cells. Furthermore, these anti-CSC drugs not only eradicate CSCs but also affect conventional stem cells in normal organs or tissues. By virtue of the enhanced permeability and retention (EPR) effect, nanomaterial drug delivery systems (NDDSs) passively accumulate in tumor tissues, thereby alleviating severe side effects toward normal viscera. NDDSs can be further functionalized with CSC-specific binding molecules to promote targeted drug delivery toward CSCs. Moreover, NDDSs have unique advantages in encapsulating CSC-specific drugs and cytotoxic agents, realizing synchronized killing of CSCs and bulk cancer cells both temporally and spatially. For these reasons, leveraging nanotherapeutic strategies to target CSCs has gained tremendous attention recently. Some ten years ago, we summarized five basic features of efficient nanotherapeutics (the five features principle), which consist of long circulation, tumor accumulation, deep penetration, cellular internalization, and drug release. Based on this design rationale, we constructed several NDDSs, including nanogels with adaptive hydrophobicity, CSC-derived microparticles with tailored softness, and tumor exosome sheathed porous silicon biomimetic nanoparticles, for targeted drug delivery to tumor. To our astonishment, these NDDSs that possess the five basic features achieve decent drug delivery efficiency toward not only bulk tumor cells but more importantly CSCs. Consequently, such nanotherapeutics as-designed based on the five features principle are potent in eradicating CSCs, even with only cytotoxic drugs, for instance, doxorubicin. Furthermore, commercialized nanomedicines, such as Doxil and Abraxane, can be endowed with these five basic features by hyperbaric oxygen therapy and therefore achieve outstanding drug delivery efficiency, potent CSC elimination, and efficient cancer therapy. These studies suggest that intractable CSCs can be tackled with a material-based approach, highlight the critical role of the five features principle in designing effective nanotherapeutics, and pinpoint the significance of drug delivery efficiency in eliminating CSCs and bulk cancer cells.