Photodynamic therapy as a local therapeutic method shows great biocompatibility in tumor therapy. However, the poor accumulation of photosensitizer in tumors restricted the therapeutic efficacy. Different from traditional chemotherapeutic drugs, some additional issues will further decrease the photodynamic therapeutic efficacy including the oxygen concentration and the short half life of reactive oxygen species. Nanoparticles as drug carriers are currently under rapid development for tumor therapy, especially in photodynamic therapy. This review mainly focuses on the design of nanoparticles for photodynamic therapy, with special emphasis on optimizing the therapeutic efficacy via the tumor tissue/organelles target, oxygen supply, and combination therapy.

Ignored damage in adjacent normal tissue is fatal especially in some specific tumor therapy such as brain tumors, but it remains a great challenge to conquer due to random drug diffusion and tumor complexity. Herein, we show that hyperthermia in mitochondria, an interparticle plasmonic coupling effect activated nanoevent, selectively strikes tumor tissues without damaging adjacent normal tissues. Spherical gold nanoparticles with a mitochondria-targeting moiety, triphenyl phosphonium, preferentially accumulated inside tumor mitochondria and reached the threshold to activate interparticle plasmonic coupling effect among gold nanoparticles, realizing selective light-thermal conversion and mitochondrial dysfunction in tumor, whereas little hyperthermia and mitochondrial dysfunction were observed in adjacent normal tissues. In vivo study revealed that the temperature increment in tumor tissue with irradiation was nearly 4-fold that in adjacent normal tissue. This subcellular organelle-templated accumulation strategy provides a therapeutic model for highly selective tumor therapy with negligible local side effects.

Photothermal therapy (PTT) is considered an alternative for oncotherapy because it has less invasive damage to normal tissues than other methods, particularly in second near-infrared (NIR-II) PTT (1000–1350 nm) because of deeper biological tissue penetration, lower photon scattering, and higher maximum permissible exposure (1.0 W cm–2). However, for achieving a higher therapeutic effect, the delivery of large amounts of NIR-sensitive agents has been pursued, which in turn enormously increases damage to normal cells. Herein, we developed peptide-coated platinum nanoparticles (TPP-Pt) to create violent damage for a given amount of hyperthermia by purposefully delivering TPP-Pt to the thermally susceptible mitochondria with minimal side effects. Mitochondrial peptide targeting endowed ultrasmall platinum nanoparticles (PtNPs) with monodispersity, high stability, biosafety, and enhanced uptake of cancer cells and priority of mitochondria, causing efficient PTT. Moreover, an in vivo experiment showed that the excellent tumor inhibitory effect and negligible side effects could be achieved with the preferentially striking thermosensitive mitochondria strategy. The mitochondria-based “win by one move” therapeutic platform of peptide-coated platinum nanoparticles (TPP-Pt) demonstrated here will find great potential to overcome the challenges of low therapeutic efficiency and strong systemic side effects in PTT.

One of the main challenges for tumor vascular infarction in combating cancer lies in failing to produce sustained complete thrombosis. Inspired by the capability of vascular infarction in blocking the delivery of oxygen to aggravate tumor hypoxia, the performance of selective tumor thrombus inducing hypoxia activation therapy to improve the therapeutic index of coagulation‐based tumor therapy is presented. By encapsulating coagulation‐inducing protease thrombin and a hypoxia‐activated prodrug (HAP) tirapazamine into metal–organic framework nanoparticles with a tumor‐homing ligand, the obtained nanoplatform selectively activates platelet aggregation at the tumor to induce thrombosis and vascular obstruction therapy by the exposed thrombin. Meanwhile, the thrombus can cut off the blood oxygen supply and potentiate the hypoxia levels to enhance the HAP therapy. This strategy not only addresses the dissatisfaction of vascular therapy, but also conquers the dilemma of inadequate hypoxia in HAP treatment. Since clinical operations such as surgery can be used to induce coagulation, coagulation‐based synergistic therapy is promising for translation into a clinical combination regimen.

The strategy that combines photodynamic therapy (PDT) and photothermal therapy (PTT) is widely used to achieve strong antitumor efficiency. Since light in the NIR-II window possesses ideal penetration ability, developing NIR-II PTT and NIR-II light triggered photosensitizer release for combined PDT and PTT is very promising in nanomedicine. Methods : We develop a novel nanocarrier (termed AuHNRs-DTPP) by conjugating photosensitizer contained chimeric peptide (DTPP) to Au hollow nanorods (AuHNRs). AuHNRs was obtained by a Te-templated method with the assistance of L-cysteine. The chimeric peptide PpIX-PEG8-GGK(TPP)GRDEVDGC (DTPP) was obtained through a solid-phase peptide synthesis (SPPS) method. Results : Under the 1064 nm laser irradiation, the nanocarrier can accumulate heat quickly for efficient PTT, and then release activated photosensitizer for real-time apoptosis imaging. Thereafter, supplementary PDT can be conducted to kill tumor cells survived from the PTT, and meanwhile the normal tissue can be protected from photo-toxicity. Conclusion : This designed AuHNRs-DTPP nanocarrier with remarkable therapy effect, real-time apoptosis imaging ability and reduced skin damage is of great potential in nanomedicine application.