This review summarizes the recent development of second near-infrared photothermal combinational nanotheranostics for cancer, infectious diseases and regenerative medicine.

Nanomedicine in combination with immunotherapy offers opportunities to treat cancer in a safe and effective manner; however, remote control of immune response with spatiotemporal precision remains challenging. We herein report a photothermally activatable polymeric pro-nanoagonist (APNA) that is specifically regulated by deep-tissue-penetrating second near-infrared (NIR-II) light for combinational photothermal immunotherapy. APNA is constructed from covalent conjugation of an immunostimulant onto a NIR-II semiconducting transducer through a labile thermo-responsive linker. Upon NIR-II photoirradiation, APNA mediates photothermal effect, which not only triggers tumor ablation and immunogenic cell death but also initiates the cleavage of thermolabile linker to liberate caged agonist for in-situ immune activation in deep solid tumor (8 mm). Such controlled immune regulation potentiates systemic antitumor immunity, leading to promoted cytotoxic T lymphocytes and helper T cell infiltration in distal tumor, lung and liver to inhibit cancer metastasis. Thereby, the present work illustrates a generic strategy to prepare pro-immunostimulants for spatiotemporal regulation of cancer nano-immunotherapy.

Cell‐membrane‐coated nanoparticles (CCNPs) that integrate the biophysiological advantages of cell membranes with the multifunctionalities of synthetic materials hold great promise in cancer immunotherapy. However, strategies have yet to be revealed to further improve their immunotherapeutic efficacy. Herein, a polymer multicellular nanoengager (SPNE) for synergistic second‐near‐infrared‐window (NIR‐II) photothermal immunotherapy is reported. The nanoengager consists of an NIR‐II absorbing polymer as the photothermal core, which is camouflaged with fused membranes derived from immunologically engineered tumor cells and dendritic cells (DCs) as the cancer vaccine shell. In association with the high accumulation in lymph nodes and tumors, the multicellular engagement ability of the SPNE enables effective cross‐interactions among tumor cells, DCs, and T cells, leading to augmented T cell activation relative to bare or tumor‐cell‐coated nanoparticles. Upon deep‐tissue penetrating NIR‐II photoirradiation, SPNE eradicates the tumor and induces immunogenic cell death, further eliciting anti‐tumor T cell immunity. Such a synergistic photothermal immunotherapeutic effect eventually inhibits tumor growth, prevents metastasis and procures immunological memory. Thus, this study presents a general cell‐membrane‐coating approach to develop photo‐immunotherapeutic agents for cancer therapy.

Therapeutic systems with site‐specific pharmaceutical activation hold great promise to enhance therapeutic efficacy while reducing systemic toxicity in cancer therapy. With operational flexibility, noninvasiveness, and high spatiotemporal resolution, photoactivatable nanomedicines have drawn growing attention. Distinct from traditional controlled release systems relying on the difference of biomarker concentrations between disease and healthy tissues, photoactivatable nanomedicines capitalize on the interaction between nanotransducers and light to either trigger photochemical reactions or generate reactive oxygen species (ROS) or heat effect to remotely induce pharmaceutical actions in living subjects. Herein, the recent advances in the development of photoactivatable protherapeutic nanoagents for oncology are summarized. The design strategies and therapeutic applications of these nanoagents are described. Representative examples of each type are discussed in terms of structure, photoactivation mechanism, and preclinical models. Last, potential challenges and perspectives to further develop photoactivatable protherapeutic nanoagents in cancer nanomedicine are discussed.

Two sets of products are formed from DNA upon treatment with Fe(II).bleomycin + O2. One set, which is believed to derive from a C-4' hydroperoxy derivative of the DNA deoxyribose moiety, includes the four possible base propenals, as well as DNA oligomers having deoxynucleoside 3'-(phosphoro-2"-O-glycolates) at their 3'-termini. The other set of products consists of free bases and alkali-labile lesions, the latter of which had not previously been characterized structurally. By use of the self-complementary dodecanucleotide d(CGCTTTAAAGCG) having a site modified by Fe-bleomycin three nucleotides from the 5'-end, it has been possible to characterize the alkali-labile product as a C-4' hydroxyapurinic acid. When the bleomycin-treated dodecanucleotide was treated with agents that effected decomposition of the alkali-labile lesion, products of the form CpGpx were obtained, and these proved useful for structural characterization of the alkali-labile lesion. Treatment with alkali produced CpGpx, where x was 2,4-dihydroxycyclopentenone. Alternatively, treatment with hydrazine provided a pyridazine derivative, and aqueous alkylamines led to formation of CpGp itself. The structures of all dinucleotides produced from the alkali-labile lesion were verified by direct comparison with authentic synthetic samples.