Introduction

Cancer therapy is one of the most significant challenges facing the health care industry today [1]. According to a recent survey, in 2020, the number of new cancer patients globally is approximately 19.29 million, and the number of deaths has reached 9.6 million. Cancer’s high incidence and mortality have led researchers worldwide to work hard to develop more accurate and rapid diagnostic strategies and effective anticancer methods [2, 3]. As an effective treatment, traditional treatments (chemotherapy, radiotherapy, and surgery) are the most commonly employed clinical treatment methods. However, patients may have a high risk of treatment failure or posttreatment side effects during or after traditional treatment [4, 5]. Among the emerging cancer therapies, photothermal therapy (PTT) utilizes the photothermal effect of photothermal agents (PTAs), which converts absorbed light energy to heat to cause thermal burns on the tumor. PTT has high research value because of its simple operation, short treatment time, and rapid recovery [6, 7]. More importantly, PTT is a highly effective and noninvasive therapy that can eliminate various types of cancer. It is well known that the ultimate goal of cancer treatment is to kill cancer cells without damaging normal cells [8,68] proposed a novel synergistic triggering mechanism to realize the self-assembly of gold nanospheres. Au@ZIF-8 does not produce photoacoustic signal and photothermal conversion capability in normal tissue. In contrast, in the presence of overexpressed glutathione and hydrogen ions in the tumor, gold nanospheres were released from Au@ZIF-8 to form aggregates and showed solid signals for imaging and effective PTT. This work provides a new strategy for designing therapeutic agents with sequential response steps to avoid interfering with diagnostic signals from normal tissue and to reduce damage to normal tissue during treatment.

However, the excitation window of existing PTT is mainly located in the visible or NIR region, with insufficient penetration depth and relatively low interaction with tissues, limiting its thermal sensitivity effect. Therefore, Professor Zhang Dong et al. [69] developed an activatable NIR-II plasmonic theranostics system based on silica-encapsulated, self-assembled, gold nanochains (AuNCs@SiO2). In this study, the optical properties were precisely controlled by the structural changes of plasmonic nanoparticles in response to the tumor microenvironment, leading to accurate diagnosis and effective treatment of tumors. In normal tissue, the self-assembled gold nanochain does not change its structure and shows photoacoustic and photothermal “OFF” states in the NIR-II region. When the gold nanochain enters malignant tumor tissue, it will obtain electron conductivity through the fusion of its chain structure, and the electric field intensity is significantly enhanced, so that the surface plasmonic resonance extinction peak has a redshift, presenting an NIR-II region of photoacoustic and photothermal “ON” states. Because of the existence of “hot spots” between the gold nanoparticles and the electronic conductivity effect of the chain structure, the photoacoustic enhancement effect is significant, and the photoacoustic signal at the malignant breast tumor is greatly enhanced to realize the specific diagnosis and PTT of breast cancer. This activated strategy can realize in situ and sensitive tumor detection while effectively killing tumors, which may prominently improve the survival rate of cancer patients and introduce a new way for optical nanoengineering to become intelligent, accurate, and non-invasive in the NIR-II window. Although all these studies reported the PTT of tumors by stimuli-responsive self-assembling AuNPs, an evaluation methodology for damage to normal tissues and skin is still lacking. To validate the possibility of specifically killing tumor cells, we established an in vitro selective photothermal transformation model (Fig. 6a), a “one facula” experiment (Fig. 6b, c), and an in vivo skin-damaging assessment model (Fig. 6d) [61]. This study is the first attempt to construct an evaluation methodology for precise PTT using in vitro and in vivo models.

Fig. 6
figure 6

(Reprinted from Ref. [61] with permission. Copyright 2022, Elsevier Ltd)

a Schematic diagram of the in vitro selective photothermal transformation model; b Schematic diagram of a “one facula” experiment; c Infrared thermal images and the temperature evolution of the tumor and skin tissue of mice treated with Au nanostar and S-AuNPs at 808 nm laser irradiation (3.33 W/cm2) at a different time; d Schematic illustration of specificity killing of the tumor cells under laser irradiation without skin damage

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In addition to self-assembling gold nanoparticles, other materials can be used to self-assemble nanomaterials at tumor sites to achieve better photothermal conversion and selective thermal burn of tumors. As a rising star in the family of two-dimensional materials, BP has attracted much attention from researchers. BP has unique optical properties, and relevant reports have proven that BP two-dimensional material can serve as an efficient photothermal preparation, and phosphorus is an essential element in organisms, making its application in the biomedical field an unparalleled advantage [70,71,72]. Recently, Han Zhang et al. [Increase the concentration difference between the tumor site and normal tissue

The photothermal conversion ability of most PTAs is in direct proportion to the concentration. Hence, increasing the concentration of photothermal nanomaterials at tumor sites is an effective method for improving the PTT accuracy. Intratumoral injection, targeting systems, biomimetic systems, and programmed targeting systems aim to increase the PTAs concentration in tumors. Although intratumoral injection can effectively cause the concentration difference between normal tissue and tumor tissue to selectively increase the temperature of the tumor site, this method cannot be directly employed for metastatic and deep tissue tumors in vivo. Additionally, many times intratumoral injections may cause to tumor metastasis. Intelligent transportation systems (targeting systems, biomimetic systems, and programmed targeting systems) enhance the uptake of tumor cells. Nevertheless, most PTAs are filtered from the body before entering tumor cells, which makes the amount of enrichment in tumor sites is far from expected. Therefore, although the method increases the concentration difference between the tumor site and normal tissue, which is feasible in theory, actual results will not materialize unless the nano-drug delivery system achieves rapid progress.

Endowing PTAs self-regulating photothermal conversion capability

Assume that PTAs have weak photothermal conversion ability in normal tissue and strong photothermal conversion ability in the tumor site. In this case, the temperature of the tumor site will selectively increase after the same enrichment amount and infrared laser irradiation, with either minimal or no damage to normal cells. Therefore, endowing PTAs with a self-regulating photothermal conversion capability through the responsive activation of PTAs at the tumor site can achieve a better precision killing effect on tumors. Although the self-regulating photothermal conversion ability of PTAs has been realized by stimulus–response systems (such as the self-assembly of gold nanoparticles or dye molecules) in vitro and animal experiments, the complexity of the in vivo environments of the body is still a significant challenge for the precisely controlled.

Prospects and challenges of clinical applications

As a non-invasive and spatiotemporally controllable tumor treatment method, PTT is still in the preliminary clinical research stage and has proven excellent anticancer efficacy in the laboratory and clinic [30, 77]. All the above mentioned methods are theoretically selective, and relevant experiments have not verified the safety of normal skin and body organs. For effective clinical translation of selective PTT, the following aspects should be taken into account: (1) provide in vitro and in vivo new evaluation methods to evaluate the ability of selective PTT; (2) improve the sensitivity of self-regulating PTAs to achieve selective PTT; and (3) investigate the long-term prognosis of selective PTT.

Although the complete clinical application of PTT has not fully emerged, it offers new hope for the clinical treatment of cancer. Highly selective PTT will render the construction of clinical PTT more refined and intelligent and become a new opportunity to develop clinical cancer therapy. With rational technological innovation and strategic improvements, there is a considerable scope for clinical expansion of the new PTT platform. Simultaneously, we hope that this review will provide valuable information and insights for future research into selective PTT.